Basic Pharmacokinetics

Basic Pharmacokinetics PHA 443
Course Content available @ http://pharmacy.creighton.edu
Schedule Spring 1999

Week of Text Content Comments
Chapters
March 15 1 –2 Introduction,
Basic Math Skills
March 22 3 Pharmacological
Response
March 29 4–5 IV Bolus, End of Material
IV Infusion for Exam # 1
April 5 Exam #1 40% To Be Scheduled
April 12 7–8 Oral Dosing,

Bioavailability
April 19 9 Clearance
April 26 10 Dosage
Regimens
May 3 Exam #2 60% To Be Scheduled
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Teaching Philosophy
Teaching is the number one priority of my Creighton mission. This is why I went to graduate school. This
is what I wanted to do all of my life. After I had graduated from pharmacy school and been a practicing
pharmacist, I applied to and was accepted into pharmacy graduate school and medical school. I chose the
former, without hesitation and without a second thought.
Availability
My students come first. I am available to students at any time. I do not have office hours. Instead, I have
a two-week running schedule on my door which tells the student when I am not available through previous
commitments. A student may see me whenever I’m available in the office or sign up for a future
appointment on that schedule if I’m not available. When in my office, the student has my entire attention
even to the point of ignoring phone calls. I have voice mail and can return calls but a student ignored is lost
forever. Obviously, this process is only a problem when more than one student needs attention at the same
time. Thus the need for future appointments.
My vision - what I do.
When asked, “What do you do?” I am reminded of a story in which the prince of a nation came upon a
construction site whereupon he asked several people what they were doing. They answered according to
their job description: “I’m cutting stone.” or “I’m mixing mortar.” The prince happened on an old stone
carver cutting a gargoyle. He asked, “What are you doing?” To which the old stone cutter replied, ”I’m
building a cathedral!” Well, I’m building competent health professionals. I teach them Creighton values. I
teach them teamwork. I teach them to be self motivated. I teach them to be self learners. We discuss
ethics; the professional, intellectual, social aspects of what it means to be a health professional graduate of
Creighton University. I tell my students that I used to teach Pharmacokinetics and Pharmacy Calculations.
Now, I use this same course content to teach Creighton values and to build competent health professionals.
It took ten years and major trauma to recognize who I am and prioritize what I do. This is what I do.!
Every morning, I get up and think, “I get to go to school today.” It’s exciting! When we talk in class about
careers, I tell the students that they will have a professional life of about 40 years. For five days a week,
fifty weeks a year, they will go to work. It had better be what they want to do! It had better be fun!
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Teaching Style – Excerpted from Presentation to American Association of
Colleges of Pharmacy – July 1997
Evolution of style - Where did it come from?
I have over the years attempted to emulate several different styles of pedagogy in an attempt to be a better
teacher. Most of us have been trained to do research, but have we been trained to teach? Most of us teach
as we were taught. Whether that is good or bad, it’s the best we can do because it's all we know how to do.
We use the tools that we learned to pass on the skills that we learned to the next generation of health
professionals. Many of us, (Pharmacy professors) come to the AACP meeting and attend the Teacher's
Seminar. We spend one day a year attempting to perfect our craft. I say craft, for craft, it really is. It
really is a learned skill and it doesn't come on conferral of a degree. We don't know how to teach content
just because we know content. I have searched for a better way to do this. What I have found,
interestingly, comes from coaching techniques as well as pedagogical literature. Several years ago, I took
courses to become an ACEP (American Coaching Effectiveness Program) certified Judo coach. Most
states recognize this program in lieu of a teaching certificate. After taking this course, I felt that the
techniques utilized in the psycho-motor domain should have counterparts in the cognitive domain and I
began to search the literature as well as attending workshops on pedagogy. I began to apply what I learned
with a gradual improvement of the outcomes of my teaching as evidenced by an improvement of overall
performance by the students and improvement of student perceptions of what was being taught as
evidenced by my teaching evaluations and student letters. A major breakthrough in my teaching style came
as a result of a one week workshop hosted by AACP in the use of case studies in teaching. What I saw was
the basics of group dynamics and the beginnings of the process described below. This seminar
significantly altered my teaching style from a professor-centered, passive-learning lecture format to an
student-centered, active-learning problem solving format.
Student Centered, Active Learning Process
What I will describe is a student-centered, active learning process applied to teaching a basic science
course. Results of this process over multi-year longitudinal retrospective study with respect to student
perceptions and performance are evaluated.
Objective: Describe (II) the role of objectives in evaluation process
I submit that we make competent health professionals. We don't have a guild system of apprenticeship to
accomplish this, like pharmacy of a hundred and fifty years ago nor do we have a completely didactic
system, but a combination of both with a didactic system designed to impart the scientific background and
basis for the rotational “apprenticeship” experience. If, in fact, our job is to make competent health
professionals, it would be reasonable to define a competent health professional. The profession of
Pharmacy has determined that there are minimum, entry level abilities or competencies necessary for
pharmacists. It is important to understand that these are not the result of some faculty member who sits in
his ivory tower saying what he thinks is important, these are what pharmacists do. These have been
promulgated as a set competency statements. The NABPLEX competency statements are one such set.
These competency statements should be the basis for the NABLPEX part of the state board exam as well as
some of the pharmacy curriculum. They are a subset of the Creighton outcomes statements which have
been promulgated by and for the faculty. These competency statements are broken down into five general
areas and further subdivided into specific activities. These should be considered goals of the educational
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process, these measurable competencies. From these, should come the course objectives, broken down as
finely as necessary to give the student the tools to do the competencies. These objectives should consist of
three parts, information necessary to do something, (Given....), an action verb (student does something)
with a level of difficulty (Bloom's taxonomy of higher educational objectives), and what is it that is to be
done. For example:
Connect course objectives to desired outcomes
Competence statement 2.00.00 Assessing prescriptions / medication orders and the drugs used in
dispensing them.
Specific activity 2.02.00 The candidate shall assess the physicochemical equivalency or non-equivalency of
multi-source drugs
Course objectives for Bioavailability:

i. Given sufficient data to compare an oral product with another oral product or an IV product, the student
will estimate (III) the bioavailability (compare AUCs) and judge (VI) professional acceptance of the product
with regard to bioequivalence (evaluate (VI) AUC, Tp, and Cpmax).
ii. The student will write (V) a professional consult using the above calculations.
Connect course exams to course objectives.
It follows, then, that the practice problems and the examinations or course evaluations should be
measurement of how well the student mastered the course objectives and nothing else. If it's not an
objective, it shouldn't be graded. Conversely, if you think that it should be graded, then it should be an
objective. The exam questions and problem sets should be linked to the course objectives and the course
objectives should be linked to the competency statements. Chaining this process back one more step, it
should be obvious that the prerequisites necessary to complete the objectives also can be determined by this
process and clearly stated.
The concept is reasonably straight forward:
1. tell them what you expect from them in detail,

2. give them practice at doing it, and
3. have them show you that they can do it.
My accountability to stick to the objectives.
I add a fourth part: If I don't follow the above three parts and put a question on an exam which doesn't meet
the requirements, the class votes and if it is agreed that the question did not meet the requirements, it is
thrown out. Note: not that it was hard, not that you got it wrong, not that you didn't think that it should be
on the exam, but did I tell them that they needed to know how to do it?; was it an objective?; and were
there practice problems? Not all possibilities can be explored in problem sets, but general problem solving
procedures can be taught. In ten years of student suffrage, not one question has ever been voted out. I do
not believe that teaching is the hauling out of voluminous amounts of facts to be sorted out and prioritized
by the neophyte student, nor is it the spoon-feeding of predigested pabulum.
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Clearly, tell the students what they are to do.
Objective: Compare (III) various levels of expectations
The expectations that you should have for the student performance would be in three arenas:
Expectations for the course

1. Level of Complexity - how much do you want them to know? (Table 2)
2. Level of Mastery - how well do you want them to know it? (Table 3)
3. Level of Instructional Demand- what student resources are required? (Table4)
These levels are really a continuum, arbitrarily partitioned into six levels with some landmarks defined. It
should be apparent that the levels should be commensurate with the student's abilities. Students should no
more be expected to perform in a previously unpracticed level than they should be able to swim when
thrown into the water for the first time. They need demonstration, practice, encouragement, practice,
evaluation, practice and then more practice.
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TABLE 2. Level of Complexity (Evans’Taxonomy of Complexity (Modified))
Cognitive Domain Psycho-motor Domain
1 Overview - Highlights of the area
Simple Motor Skills: easy repetitive motions
2 Introduction: Some perspectives and Compound Motor Skills: Multiple motions not
principles necessarily repetitive
3 Perspectives and some essential principles Applied Motor Skills: care and beginnings of
dexterity required
4 Intermediate : Most essential principles and few Involved Motor skills: coordinated, multiple
topics in depth manipulations
5 Advanced: All principles and majority of topics in depth Complex Motor Skills: high degree of dexterity required
6 Most Advanced: Great depth in virtually all subjects Most Complex Motor Skills: strength, endurance,
dexterity needed
TABLE 3. Level of Mastery (Bloom’s Taxonomy of Higher Educational Objectives)
Cognitive Domain Psycho-motor Domain
1 To Know, Recognize information / material Slow and awkward
2 To Comprehend, Recall information / Not as slow with moderate precision and accuracy
material
3 To Apply information, do calculations
Speed, accuracy and precision improving
technical skills but still substandard for entry level
4 To Analyze a body of knowledge identify Methodical and meeting all minimum standards of
relationships precision and accuracy
5 To Synthesize put together information in new ways
Methodical processing declining and finesse
increasing as well as accuracy and precision
6 To evaluate judge the worth of an idea Good speed, with precision
accuracy and finesse
TABLE 4. Level of Instructional Demand (Evans’Taxonomy of Instructional Demand (Modified))
1
Little or no initiative required, virtually no outside class time needed
2 Moderate initiative and concentration, outside class time approaches in-class time
3 Increased level of initiative and concentration required; begin independent learning; outside class time begins
to exceed in-class time
4 Average level of initiative and concentration independent learning required; outside class time about twice in-
class time
5 Substantial initiative, concentration, independent learning as well as outside class time required
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Intense initiative and concentration required, in-class time minimal
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Getting the student to buy into your expectations is critical for his/her success.
Level one in complexity, mastery and demand might be boring to a first year pharmacy student and be
considered a “nothing” course, but if your objective is to simply expose the students to the job
opportunities available to a pharmacist, for example, level one is appropriate. Setting appropriate
expectation levels is essential and making the students aware of the expectations is critical. This latter
process is most difficult. Students have a learning process which has served them well in the first two
years of undergraduate courses. In these courses the mastery level was wrote memorization (Bloom's level
I), a little essay (level II), maybe some application (Level III), and occasionally, very rarely, some analysis
(level IV). They have gotten good grades by cramming the night before the exam, which works well with
level I and decreases in effectiveness as the cognitive expectations increase. Now, in professional school,
the mastery level expectations are Level IV for many of the courses and by the time they are on rotations,
level V. Interestingly, even when these expectations are discussed in detail, the students memorize the fact
that they need to operate at level IV and are quite good at regurgitating the taxonomy, and the definitions (a
Level I cognitive skill), but complain bitterly when asked to perform at that level (do one on an exam.)
“You never showed us how to do that variation!” That’s right. If I had showed them that variation, it
wouldn’t be a Level IV. It would be a Level III.
They are not prepared to operate at these levels. They are, for the most part, devoid of experience in these
levels. They are comfortable being passive learners in which the faculty lecture and they take notes and
memorize the notes for the exam. Getting them to understand that, if they continue on this course of action,
they are doomed to failure is difficult and in many cases takes a “wake up call” of poor performance which
galvanizes them to change behavior. Those that can not, or will not because they cling to old behaviors, are
eliminated. Each year, we lose several bright, young students who can't or won’t make the transition.
Thinking is hard. Thinking is painful. To quote Tom Hanks from “A League of Their Own,” “Of course
it's hard! If it were easy, everybody could do it!”
Why might students fail?
I believe that there could be four reasons for failure:
Student is not intelligent or prepared enough to do his/her job.
In the first reason/excuse, I would offer that our student pool is such that we take the best of the best. At
Creighton School of Pharmacy and Allied Health Professions, we routinely have 9 applicants for every
seat. Our incoming classes GPA is > 3.2 with many having attained a Bachelor’s degree. These folks are
educable. I've found that they are neither stupid nor lazy. Content ignorant, yes, but that is why they are
here and that is fixable. Give them the tools, point them in the right direction, and get out of their way.
Faculty refuses to do his/her job.
In the second reason/excuse, I would also offer that I routinely get students who have failed a comparable
course at other universities in my summer session. These students not only pass, but learn with enthusiasm
and get A's in a course that they hated before. And before you chalk it off to “a nothing course,” take a
look at the exams. One student from another university called me to tell me of her experience upon
returning to her home college. Her instructor asked her how she did and when she told him that she earned
an A, his response was that it must have been an easy course. What does that tell the student about his
opinion of her abilities? She whipped out the final exam and said, “Here, you do it!” His response, upon
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looking at the final was, “Oh, S---! - You've got to be kidding.” This faculty member routinely fails 20% of
the class. I wonder.
Student refuses to do his/her job.
In this third instance, I believe the students have motivation to perform well. They, after all, have chosen
pharmacy as their profession. In most cases, no one holds a gun to their head (although I can remember
two cases in which this was not true. Once, I had a young lady who dearly wanted to be a dancer and her
parents would pay for college only if she would become a pharmacist. She's now a dancer. A second
student didn't want to be a pharmacist but again, parental pressure. He's now a happy, professionally
satisfied pharmacist in Oregon.) If they don't want to work, we have failed to motivate them, interest them,
or show them the relevance of what we teach. In a recalcitrant few whom I am unable to motivate, even
when they complain, they recognize what is happening and complain all the way down to failure. One
student's evaluation stated, “I hated this course. I had to do it all by myself.” Right on! All learning is
active. If the only active part of the course is the night before the exam, how much can you learn,
particularly at the higher mastery levels. It has been said that people remember 10% of what they hear (I
wonder if it's that high if you are the sixth lecture of the day or right after lunch). I submit that they retain
greater than 90% of what they do, actively do, in concert with their peers.
Students experience problem outside their control.
In a few cases, students who perform poorly, do so as a result of some psychological emotional, monetary
or physical problem which must be solved before and meaningful learning can take place.
Whose education is it anyway?
Objective: Assess (IV) differences between traditional passive and active group-based learning
The crux of the matter is responsibility. The main difference, I believe, between active and passive
learning is shifting the responsibility for the education from the professor to the student. In the professor
centered, passive process, it's the professor's responsibility to set and adhere to a time-line. It's his/her
responsibility to “cover” the material. It becomes a game by the student to get the faculty “off-track” so as
not to cover so much for the exam. When the students are successful, the faculty, either covers less or more
often covers the same amount, only faster. The professor assigns readings with the inevitable question, “Is
that going to be on the exam?” If you tell them it is, and it isn't, they'll never read the book again. If it is,
then you're too picky and you didn't explain it in class. Another part of the game is to ask “Is this relevant?
I don’t do this at Walgreen’s”. It's the professor's responsibility to make up the exam and the students'
game to find out what's on the exam and to argue for points after the fact. Its the professor's responsibility
to come to class prepared, give an organized, coherent lecture, and possibly answer questions. It's the
students' responsibility to take (or get from someone who came to class) a few notes which are ignored
until the night before the exam.
When students take responsibility, students win.
In the student-centered, active learning approach, it's the student's responsibility to set and adhere to a time-
line. It's the student's responsibility to cover the material. It's the student's responsibility to come to class
prepared. (You might argue that these have always been student responsibilities. I submit that in this
active learning process, they accept them and run with it and, if they don't, the members of their group
drag them kicking and screaming into compliance.) Last year's class voted for unannounced quizzes
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because they felt that there were members of the class who were not coming to class prepared. It passed
unanimously! They are given the opportunity to the set the exam schedule. From these, the faculty sets
the content and the weights. The student is given the detailed objectives, reading materials, references, and
practice problem sets. They set their own time lines to attain mastery of the objectives. From the
objectives, the faculty create the exams. This obviates the eternal question, “Will this be on the exam?”
What ever they have to do, where ever they have to go to get competent in an objective is their
responsibility. If they have to read the book, if they have to go to the reference material, if they have to
work a hundred problems, so be it. A second year student retold a first year's conversation that she
overheard, in which the first year was complaining that I had given out 90 problems to review by the
following week, to which she replied, “and you had better do them, too.”
This is a competency based educational experience.
Competence must be reached by the end of the course. I personally don't particularly care if that occurs
early or late in the course. If, for example, the class decides on two exams, then in my course, competence
of the first exam material can be shown in a special version of the second exam whereby students who have
failed to show mastery in the obtaining of the pharmacokinetic parameters from data sets must do so in
order to proceed whereas those who have shown mastery at the appropriate level are given those
parameters for their use in developing a dosage regime. If they, then, have gained competence in the first
section material, taking this exam replaces the previously unsatisfactory grade with the grade earned on
this section of the exam. If they haven't gained competence on the first section, they can not do the second
section as answers from the first section are used as input for the second section. This special exam is
required for the students who previously failed to show competence (D or F) and optional for anyone else.
Pharmacy is a lock step curriculum. What that means is that all the students take the core courses at the
same time. The corollary is also true. The whole class is off at the same time. An interesting phenomenon
has arisen in my classes. Second year students are off and in the building when the first year students are in
Pharmacy Calculations. The second year students voluntarily come into the class and work with the P1
groups and don’t need to look at the book to assist the P1s in problem solving! The third year class is off
when the second year class is in Pharmacokinetics and the same thing is happening. Competence is not that
you could do it on an exam but when you can explain it a year later!
To recap:
1. Expectations: tell them what is expected - in detail, with specific objectives and appropriate discussion
of mastery required.
2. Employ skills: Give them resources to complete the objectives (reading materials, references, problem
sets with answers.)
3. Evaluate Mastery: of those specific skills learned and objectives met.
How does a faculty do this? Group Based Learning is the key! In medicine, the era of the mad scientist,
locked up in his tower laboratory discovering the cure for Cancer or some other dreaded disease is gone
forever. Almost all significant scientific advances come as a result of teamwork. Why not teaching?
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Teaching Process - Group Based Problem Solving
Objective: Describe (II) the process of initiation of group based learning
Establishing the Process
In this changing world of health care, pharmacists are being challenged to enhance their clinical and
problem solving skills. Students of pharmacy must develop these skills so that they may help fulfill the
profession's emerging role in pharmaceutical care. At Creighton University students are introduced to
group-based learning in their first professional year in Calculations and in their second year in
Pharmacokinetics in my courses and several faculty are beginning to apply this pedagogy in their courses.
Being able to work in a team, being an active, contributing member of a team is a Creighton value. It is
one of the other than content things that is stressed at Creighton University. The transformation from
traditional, didactic, professor-centered passive learning to student centered active, group based learning is
often dramatic and always traumatic - for both the student and professor! It will not go well for the first
four weeks if the student has never experienced this process. Don't give up. It will be worth every second
of agony that you go through. (I have found ways to shorten the first, troubled stages of group growth.
Constant communication and defining expectations is the key.) The first time I decided to do this, I
consulted with my chairman and told him that I was going to try a new teaching style and to be ready for a
lot of complaints and possibly bad evaluations at the end of the semester. Then I told the class how it was
to go, I held the first introduction, gave over the keys to the kingdom, and promptly when into the
bathroom and threw up! How could I turn over the responsibility for their education to children who are
always looking for the easy way out? Well, I tell you that it succeeded beyond my wildest dreams.
Seriously, it’s not for the faint hearted. It requires major shifting of paradigms on everybody’s part, but it’s
worth it if you don’t give up.
“Toto, I've a feeling we're not in Kansas anymore!” - Dorothy, Wizard of Oz.
Objective: Describe (II) the responsibilities of the various players
Who are the Players?
Facilitator: Person coordinating the course. (Read Professor in other style.) Person who assists the
students upon request. S/he would direct students to references and help them organize and connect up
what they read.
Quality Team Leader (QTL): Student group leader / ombudsman to facilitator from group. (See QTL
Responsibilities at the end of this section on Teaching.)
Group: Collection of four students assigned to work together by the facilitator. Once a level of
performance is reached, they become a team.
Team: A well organized group who can work together outside of class to meet common goals.
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First day of class
Facilitator introduces the course, outlines his expectations (of both the students and the Quality Team
Leader, QTL), hands out course materials and detailed objectives. He outlines the ground rules, which
are: the groups have majority control governing number of exams to be given, exam dates, and if they
want quizzes. Items that are not negotiable are overall course time table, overall course content, number of
questions on exams, weight of exams or exchanging group members. Attendance is not optional - it's
mandatory. The group needs to be together to function.
Students are randomly assigned to groups of four by a deck of cards. Each group is a card value and each
student is a suit. e.g. the Aces are a group and each student is permanently assigned a suit. The students
are given an “icebreaker” exercise to get them to learn more about each other. Each group selects a quality
leader to serve as a direct liaison between the group and facilitator.
The students are expected to read the book and references, come to class prepared and bring the tools
necessary to work the problems; i.e. ruler, log paper, pencils, etc. They meet within their groups, discuss
the required reading, correlate the specific objectives and the reading material and begin working on
problem sets. In addition to the problem sets each individual student is responsible for several library
assignments in which they are required to calculate the pharmacokinetic parameters from the data using the
tools learned in class. The student is then required to communicate in writing the results of such
calculations with a suitable commentary regarding differences and interpretations. Each of the above
sections is designed to bring the student an understanding of the information and the processes
necessary to operate as a competent professional in the area of pharmacokinetic evaluation and
consulting. Consequently, the course evolves from a quantitative, manipulative mathematics course to
a course which stresses communication skills. Consults will be graded not only on content (the proper
dosage regimen for the patient) but also grammar, punctuation, spelling, organization and neatness. The
student may have the best medical information in the world, but if it is poorly executed, it will be
ignored.
Weekly, the students are asked to provide a one minute summary of the topic consisting answering the
following questions:
Weekly Status Report

1. What was the main thrust of the study section?
2. What was clear about the study section? What was done well?
3. What was unclear? How could it be done better?
This provides a running monitor of effectiveness as well as a framework of what to stress in the reference
materials. This feedback is essential to get the mood of the groups and to address major concerns.
Furthermore it serves to provide a continuous quality improvement aspect of the course - it is constantly
evolving and refined each time it's offered. (See Weekly Status Report at the end of this section on
teaching.)
What does the facilitator do?
The facilitator roams around the groups to answer questions, guides groups to resources to clarify concepts
and start them on derivations of equations if needed. After each section, the facilitator will give an
executive summary of the essential material the student needs to process for the exam, if requested. It is a
short lecture (overview) designed to tie in key concepts in order to enable the student to visualize the big
picture - how small pieces fit into the larger whole. An important piece in the scenario is timing. The
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executive summary is not done at the beginning. It is not a lecture. If done before the student reads the
material, it becomes a replacement for reading the material and since it is not designed as such but designed
only to tie together the reading and emphasize salient points, the process fails. In this case, the operative
thought is: “No question is answered before it's asked.” The facilitator must wait until the student gets
stuck and needs to seek assistance. When the same question shows up in several groups, the facilitator
halts the group activity and gives the executive summary. At that point, an interesting phenomenon occurs.
As the facilitator ties things together, students are listening, the facilitator gets positive feedback by facial
expressions and head bobbing and nobody is taking notes! They are ready to hear what you have to say.
They have already created the storage space in their mind. They are not stenographers who blindly take
every word down in hopes of understanding it later. They understand it now!
Facilitator responsibilities include training the QTLs, initiating regular meetings with QTLs, helping
identify and solve problems within groups. He focuses on process, not content during the meetings. He
might intervene to clarify/correct/teach if discussion deviates too much from what is reasonable. He may
also institute changes in the course if a particular issue seems to be a major problem.
The facilitator should only intervene in a group if and only if the following conditions exist: the group is
dysfunctional; clarification, feedback, summarization, or encouragement is needed; the group needs a
formula/tool that the facilitator knows and can suggest where it can be found. Don't just give the answer.
Show them how to find it. OTHERWISE HE IS TO SIT STILL AND BE QUIET!!!!!!
The facilitator attitude must be (and perceived to be) honest, genuine, respectful, humble (here to serve, not
dominate). He must remain patient and detached, always attentive (listens to everything said, and watches
what goes on). Studies body language and gives careful attention to quiet members. He must stay at a
high energy level (groups will tend to set pace with the facilitator). He must communicate on a one-to-one
basis as well as to the whole class. These must perceive that the facilitator is listening! Most students’
perceptions were favorable about the facilitator. Most students recognize that this is not an easy task:
(Student Quotes from evaluations are added in italics.)
“Dr. Makoid is an outstanding educator, he takes a tremendous amount of pride in what he does. His availability to the students
amazes me, I have never seen this.”
“I think you were very fair and extremely generous with your time.”
“I hope to get a C, but whatever my grade turns out to be I am proud of it because I know that I earned it.”
“You made a very difficult subject very easy to understand.”
“My first really relevant course and my best at Creighton so far.”
“I think he is a great teacher. Always answered my questions and encouraged the students to do their best. He also respects the
students as tomorrow’s professionals.”
However, there are some students who get very hostile about this type of learning. For example:
“This is a worthless approach - by the end of the first class I knew if I was going to get anything from it, it would come from self-
teaching.!! (Isn’t this what I was trying to do?)
“We pay him to teach us, not to teach ourselves! Maybe we should of been paid, instead of him.”
“I think this is an easy way for professor’s to get out of teaching!!”
I might suggest that this is definitely not a teaching cop out. It takes considerably more effort than the
traditional didactic process. In the professor-centered, passive-learning lecture format, I would, for a 2
credit course of 100 students, give two lectures of 50 minutes each. In the student-centered, active learning
process the students are broken into four sections of 24 each (six groups of four.) I am with those six
groups for two and a half hours each section plus an extra two hours every week that is an open section for
anyone to come and ask questions. In a session, each group of four has my entire attention for an average
of about 20 to 30 minutes. Some groups who are doing well don’t need the entire time, while other groups
need more than the average. I do, however, sit with each group for every session, listening to the
discussion and giving direction if necessary. I will also offer that active learning is not some weird process
that I thought up. There is over fifty years of competent research in the educational field proving
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conclusively that this method is substantially better for the student with significant improvement of
comprehension as well as retention. This is also apparent in data from this class at Creighton University.
What do the QTLs do? Kizen.
The Quality Team Leaders (QTL) and the facilitator begin meeting on a regularly scheduled date and time.
They meet throughout the semester to resolve group issues and problems. The Japanese term for this is
“Kizen.” It means to continuously improve. What better way to improve than to ask the people involved,
the students, what is a barrier to your learning? Lets remove it. Last year the students voted to have
unannounced quizzes because they felt some members of the teams were not coming prepared to work. (If
I had instituted that, I’d be persona non grata. Go figure.) This year, the students suggested that we meet
in a room with tables rather than desks -- done. They suggested blackboard for the groups would be useful
-- a little harder, but we got it done. Westerners tend to make giant leaps and sit back on their laurels,
whereas the Japanese constantly work, constantly make things better. We want to constantly make the
learning experience better. It’s kind of like the tortoise and the hare and you know who won that race. The
quality team leaders are given instruction and reading materials regarding their responsibilities. It is their
job to make the group work. It is important to note another cultural difference at this point. It is
commonplace for Westerners to place blame when something doesn't work. Eastern philosophy is not the
least bit concerned with blame; the focus is problem solution.
Problem solving, not placing blame, is important.
It shifts from a person problem to a process problem which is completely non-judgmental. The QTL
members bring suggestions which are discussed and voted on by the entire QTL team. If passed, it is
brought before the class and voted. If passed, it is implemented immediately. Personally, I have always
thought that student evaluations at the end of the semester have only served to allow the student to vent
his/her spleen about some thing that didn't go right in the course that the teacher doesn't know about until
it's too late to do anything about it for this class. This process allows the student to remove the barriers
from his/her learning when it will do her/him some good. Students feel that the faculty has listened and are
more responsive to listen to the faculty.
Quality Team Leader's responsibilities are to attend all the quality meetings with the facilitator or make
arrangements to have another of their group take their place if they cannot make it. They are to participate
as a group member as well as ensure that the group is functioning. The quality leader must exchange
information with the facilitator concerning problems encountered within the group so that they can be
addressed and corrected. They are responsible for the timeline between learning the material and exam
dates. They help establish and abide by guidelines given at beginning of course.
Quality Team Leader attributes include an outgoing friendly nature and a willingness to support the process
as well as a sense of personal responsibility to ensure the process is working. They must be able to
communicate verbally within the group and with facilitator and serve as a role model.
What do the students do?
Students are to participate as a group member and teach one quarter of each exam material to their group
members. This forces each member to be an active participant or risk the wrath of their peers. Obviously,
they are to read the material, be prepared to ask and answer questions and help solve the problems. They
are to seek assistance from the facilitator when the group gets stuck.
13
It is interesting to note that some students secretly, resolutely hold on to their paradigm of the professor-
centered, passive-learning process. Upon poor performance in the class, they lash out against the
facilitator, QTL, and the group even after reporting weekly to the QTL that everything is going well, the
group experience is positive and that they have no complaints. I believe that it is simply a sign of
immaturity to seek to place blame for your failures rather than to accept the consequences of your actions.
They will learn that this behavior is counter productive to their goal of becoming a competent health
professional.
“You can observe a lot just by watching” Yogi Berra
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Teaching Process - Group Growth Stages
Objective: Describe (II) the stages of group growth
Group Dynamics: Learning to work together.
In group-based learning, the members must work out personal differences, find strengths on which to build,
balance commitments of this class against the demands of other classes and work, and learn how to
problem solve. Pharmacy students are competitive by nature, and in traditional didactic learning they have
relied solely on themselves. A major obstacle to overcome is to change their thinking of “me” to thinking
of “us” and to take the responsibility of teaching a portion of the material to their peers. This is an
important step in realizing that someday they may become part of a team in which they must educate other
health-care professionals in order to improve patient care. As the team matures, members gradually learn
to cope with the emotional and group pressures they face. As a result, the group goes through fairly
predictable stages.
Stage 1: Forming
This is a stage of transition from individual to member status - like hesitant swimmers; they stand by the
pool, dabbling their toes in the water. They don't believe that this is for real. They demand a lecturer,
someone to read the book for them and tell them what to do. Their feelings may include excitement,
suspicion, fear, and anxiety about the course ahead. Student comments regarding this stage include:
“In the beginning I was apprehensive, but at the end of the class comfortable.”
“I felt very defensive at the beginning but better now.”
“In the beginning I felt intimidated, at the end of the course I felt like I could be an asset to my group.”
Because there is so much going on to distract member's attention in the beginning, the group accomplishes
little, if anything.
Stage 2: Storming
Storming is probably the most difficult stage for the group and the facilitator. It is as if the group members
jump in the water, and, thinking they are about to drown, start thrashing about. They begin to realize the
class is different and more difficult than they imagined, becoming testy, and blameful. “It's all Dr.
Makoid’s fault. If he would only teach us like he's supposed to, it would be OK!” At this stage they are
impatient about their lack of progress, but too inexperienced to know what to expect or what action the
group should be taking. At this point they resist the need to collaborate with their group and because test
time is rapidly approaching, panic and revert back to their norm - I can do this by myself - and I can wait
until two days before the exam to do it!!!!! This phase unfortunately takes place before the first exam. Do
not give in to the desire to revert back to spoon feeding the poor dears. Remember “Knowledge maketh a
bloody entrance!”
Stage 3: Norming
This stage forms rapidly after the first exam results are posted. During this stage, members reconcile
competing loyalties between themselves and their group and their responsibilities. They accept the group,
15
the ground rules, their roles in the group, and the individuality of fellow members. Emotional conflict is
reduced as previously competitive relationships become more cooperative. Group members begin to settle
down and start helping each other. The change is significant to an observer - they become more relaxed,
enjoy themselves, and begin to work together. As one insightful student wrote, “I wasn’t giving all I could
on the first exam, thinking I could pick it up days before, but I was sadly mistaken. Groups are a good
thing. I don’t think I was fully taking advantage of them, but I hope to improve in that aspect.”
Stage 4: Performing
By this stage, the group has settled its relationship and expectations. The team is now an effective, cohesive
unit. You can tell when the students reach this stage because they get a lot of work done. Complaints are
rarely made. In fact, when asked to give their group mates a percentage score based on their group activity
- everyone unanimously gives their group members a 100%!!! They have moved from passive to active
learning. One student's response to the facilitator's question of “How are you doing?” was “We’re busy.
We’ll call you if we have any questions.” You can tell when you are there. No questions!
At this stage they may also have insights into personal and group processes, and a better understanding of
each other's strengths and weaknesses. For instance, when surveyed, a majority of students stated that their
greatest individual weakness was that they felt they were slow to understand/learn. They perceived that the
group’s major weakness was that they could not meet as much as they wanted to outside of class.
COMMUNICATION
“I know you believe that you understand what I said, but I'm not sure you realize that what you heard is not what I meant”
1. “In the beginning I was apprehensive, but at the end of the class comfortable.”
2. “I wasn’t giving all I could on the first exam, thinking I could pick it up days before, but I was sadly mistaken. Groups are a good
thing. I don’t think I was fully taking advantage of them, but I hope to improve in that aspect.”
3. “I felt very defensive at the beginning but better now.”
4. “I'm busy. I'll call you if I have any questions.”
5. “In the beginning I felt intimidated, at the end of the course I felt like I could be an asset to my group.”
6. “It's all Dr. Makoid’s fault. If he would only teach us like he's supposed to, it would be OK!”
7. “I was very skeptical concerning the teaching method, especially at the beginning.”
8. “Working in groups was definitely beneficial. I think I learned a lot more than I would have learned on my own.”
9. “I felt the course taught me to think more on my own.”
10. “We pay him to teach us! Not us teaching ourselves! Maybe we should have been paid instead of him!”
11. “Working in groups helped me get a better understanding for it because when I talked about it, I found I really knew what I was
doing. I think it was good just the way we did it.”
12. “Our group has hard time going at the same pace. Some members are ready to jump into the problems with no idea about the
concept while others try to read up on it because they don’t understand.”
13. “The group thing needs a lot of work.”
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Barriers to Overcome
1. Physical
A. This method of instruction will not work well in lecture amphitheaters. Even in rooms with separated
desks, this does not work well. Students complain there is not enough desk top space, and they are
distracted by other groups talking. The ideal atmosphere includes a room divided into discrete sections for
each group with a large table and blackboard for each section.
B. In retrospect, a common complaint of spring/fall semester students is that they don’t have enough time
to work together. This method of teaching is not well suited to 50 minute periods. The ideal scenario
seems to be blocks of time - for instance, summer groups seem to coalesce faster because they meet for 3
hours per day. They have time to accomplish problem sets without running out of time.
2. Mental (Refer to Appendix E)
A. Student Attitude - What I call the John Wayne attitude: I can do it all the night before and teacher will
tell me everything I need to know for the test among others.
B. Facilitator Attitude - You just got to believe and exude confidence in this style of learning. If you
don’t, it will crash and burn.
3. Materials
A. Objectives must be and perceived to be clearly stated and detailed. Approximately 95% of students
surveyed agreed that they felt the course objectives were clearly stated. In addition, 98% agreed that the
examinations given reflected the course objectives.
B. Content of the class must be organized in a step-by-step fashion so that the student is always building
his knowledge base.
“Paradigms are significant problems that cannot be solved with the same level of thinking with which we
created them” EINSTEIN
It is possible to facilitate the group growth into stage four if the students are told what to expect about the
process as well as monitored and behavior corrected as it develops.
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Teaching - Student Perceptions of the Process
Objective: Discuss (III) the student perceptions and corresponding supportive data derived from
group based learning experience
Student perceptions of group-based learning:

“This is the first course that I've been given credit for being able to read.”
“Wonderful feeling to have an understanding rather than memorizing for a course.”
“I feel more driven and challenged.”
“This teaching style makes you think and learn for yourself. This is the real world.”
“I thought the new style of class instruction helped me learn more effectively.”
“I have never felt this good about a class and so confident.”
“Overall it has prepared me to think more on an individual level, which in some cases in the profession you will have to do that.”
What to expect:
Expect variability in the classroom. In traditional didactic lecturing, the classroom remains a static
environment, however in group based learning each class becomes a new adventure in teaching. Each
group progresses at a different rate and has unique characteristics.
Expect that the groups may fail in the beginning and be ready to accept their failure. It is extremely gut-
wrenching to watch this, but a valuable lesson is learned after the exam: “Let's start working together!”
Expect that the groups will no longer need you when they approach Stage 4. It can be very disconcerting
for a facilitator who wants to be needed!
Expect that other faculty may consider group based learning after they come to observe the process.
However, expect also that some may run away as fast as they can!
With respect to the students expect better performance, higher grades, greater retention, improved attitude
toward field, improved attitude toward facilitator.
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Teaching - Supportive data - Student Performance
Does this process work?
Group work outside class increases prior to the night before exam. This can be readily observed and
substantiated by the fact that the students who do not work within a group environment or groups that do
not meet outside of class time do not perform well on exams. This is supported by student comments and
self-evaluations.
TABLE 5. Supportive data - Exam Scores
Passive Learning Group Active Learning Group
1991 – 1993 1994 - 1996
(n =273) (n = 255)
Exam 1 78.6 85.3
Exam 2 82.2 92.7
On the average, exam means increased one letter grade without any change in content, complexity or
mastery requirements.
“This was the first time that I went to bed at 9:00 P.M. the night before an exam.”
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Teaching - Supportive Data - Student Perceptions
TABLE 6. Student Perceptions of their performance
Exam 1 Exam 2
Higher 27% 57%
Same 14% 11%
Lower 21% 11%
No Reply 38% 21%
Do the students think it works?
Since most students do not have a comparison between how they would have performed in a traditional
pharmacokinetics course in comparison the group-based course, they have difficulty in perceiving how the
group has affected their grade. There are, however, a few students from other universities who have had
the “opportunity” to experience similar courses differing only in active v passive style. At first, they are
apprehensive and try to do it the passive way. They even tell me that at _____ university, we did it by
passive teaching style (my translation). I tell them that the operative definition of insanity is to do the same
thing over again and expect a different result. I ask them to give this process a chance and to try something
new.
It was interesting to compare IDEA evaluation responses for traditional (passive) students versus group
based (active) students. In both subject matter mastery and the development of general skills, students who
took the traditional course in the summer mirrored group based learning responses. It has long been my
perception that the summer classes performed better than the regular semester. Everything I did was the
same in both classes, so the differences were not something that I did. In 1991 through 1993, I observed
that in the summer, students came to me in groups to answer questions while in the regular semester, they
came singly. Voluntary group learning was the only difference! Thus, in the subsequent tables, Passive
Summer is separated from Passive Semester. It can be seen that Passive Summer Session more closely
resembles the active groups because they, in fact, voluntarily formed active study groups.
TABLE 7. Student Perceptions from IDEA Evaluations Regarding Development of General Skills
1 3 4 5
Strongly 2 Neutral Agree Strongly
Disagree Disagree Agree
Passive Groups Active Groups

Semester Summer Both
Thinking and 4.0 4.3 4.2
Problem Solving
Creative Capacities 2.4 3.5 3.7
Effective 2.0 3.0 3.0
Communication
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TABLE 8. Student Perception from IDEA Evaluations of Questions regarding Subject Matter
Mastery
1 3 4 5

Factual Knowledge 3.7 4.1 4.0
Principles and theories 3.8 4.1 4.0
Professional Skills and 4.0 4.2 4.1
viewpoints
Discipline’s Methods 3.2 4.0 4.0
Some student perceptions:

“This course required a lot of hard work and thinking. Initially it was frustrating, but after working hard the concepts fell into place
and soon I was surprised at how much I learned. I became self-motivated to work even harder and found the concepts fascinating and
almost fun.”
“Excellent class and instructor. It challenged my level of thinking and problem solving.”
“This course involved a lot of time and effort, which made it very challenging. But in the end, it pays off.”
TABLE 9. Student Perceptions from IDEA Evaluations Regarding Development of Personal Skills
1 3 4 5

Personal Responsibility 3.3 4.0 4.1
It is not surprising that the students perceive an increase in personal responsibility in group based learning.
When asked if the group experience made them a more responsible and knowledgeable group member,
>95% agreed. In reply to the question of what was your group’s greatest strength, a majority of students
replied that their group worked well together - members were willing to help each other, communication
was good, and they worked hard to accomplish the given objectives. When asked what strengths they
gained through the group experience, the students replied: understanding, confidence, communication
skills, time management, listening to others.
TABLE 10. Student Perceptions from IDEA Evaluations Regarding Student’s Self Rating
1 3 4 5

Improved Attitude 3.6 4.0 3.9
toward Field
Student comments:
“After taking this Pharmacokinetics course, I have a more confident feeling about going into the pharmacy profession. I feel that I am
competent and secure in deciding what's best for a patient in regards to dosing regimens.”
“Would like to take advanced kinetics class - am very interested in the field.”
“I was not looking forward to taking this course, however, I have gotten more from this class than I ever thought I could have. I
actually enjoyed kinetics, the method in which the course was taught, and then being able to solve the problems. I now have a very
positive attitude toward kinetics and look forward to taking another class.”
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Teaching - Appendix A - QTL Responsibilities
Congratulations! You have volunteered (or have been coerced) to assume the role of a Quality Team
Leader (QTL). This is a position of leadership within your group and with it comes some added
responsibility. The purpose of this handout is to outline your role as QTL - your duties, and the
expectations I have for you. Do not panic. I realize that for most of you this process is new and different.
Group based learning is rapidly becoming the teaching method of choice for several important reasons -
students understand better and retain longer knowledge that they have actively learned, and they usually
perform at a higher grade level. The main difficulty students have with this type of education is that they
have never been responsible for learning or teaching each other within a group environment. Many
students resist group learning and rebel or they may not know how or where to begin. Another obstacle is
establishing and maintaining a timetable in order to get through the material before the exams. A major
dilemma you face will be focusing the group’s energy and attention to work through concepts and problems
in time for the exams.
QTL Responsibilities:
1. Attend all quality meetings or make arrangements to have another group member take your place if
you cannot make it. This is important to keep lines of communication open between each group and me.
You can voice your group’s concerns, bring suggestions to discuss and vote for changes. You will be
responsible to take back meeting information to your group.
2. You are to participate as a group member - being a QTL does not excuse you from taking on your
share of group responsibility. Set an example to come to class with the required materials and be ready to
work.
3. Be a role model - be willing to support the process. Your fellow group members will take their cues
from you. We all know attitudes can be as infectious as the common cold - Keep yours positive! If you
have concerns or feel yourself down, talk with me.
4. Communicate with me about any problems or concerns within your group. This is not “ratting” on
your peers. Our (mine and yours) major concern is to ensure that the groups are functioning to the best of
their abilities, that they are meshing together, learning the material, and working on the problem sets. If
your group (or a particular member) is not functioning well, everyone loses time and knowledge. My job
as facilitator is to help get the group working - BUT this can only happen if I know that a problem exists.
This information will remain between us and confidential.
5. You will be responsible for creating your group’s timeline for learning each portion of material
before the exam. Your class determines the date and time of exams but the content is not negotiable. You
need to work within your group to establish how much time you need to devote to each portion so that your
group will be done with the material before each section exam. You will have to monitor your group’s
progress and keep them focused. Tell them what is to be covered next, assign problems to members, and
keep moving forward. Not all groups will work at the same speed. What is important that all the
designated material is covered well before the exam - Do not wait to learn it all the last 2 days before the
exam! It won’t happen!
6. You are responsible for turning in a weekly status report. It is important for us to communicate both
verbally and in writing. I need to know how everyone is progressing through the course material and
within the group. If you have any concerns/problems that you feel cannot be addressed in the quality
meetings, write them down on this report.
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Teaching - Appendix B - QTL Weekly Status Report
GROUP:___________________ LEADER NAME:_____________________
MEMBERS PRESENT:_________________________________________________
MEMBERS ABSENT:__________________________________________________
DATE:__________________ LAB SECTION (circle one) A B
The purpose of this weekly status report is to keep the lines of communication open between you, the QTL
and me, the course facilitator. Honest, open and constructive dialogue (written or verbal) between us will
result in a class which is continuously improving.
GROUP PROCESS - COMMENTS/CONCERNS/SUGGESTIONS:

What can be done to help your group accomplish the course objectives? Please list any suggestions or
constructive changes that you or your group members may have to improve in this area. Is your group
working together? If not, what can we do to make things better?
COURSE CONTENT - COMMENTS/CONCERNS/SUGGESTIONS:

Is the course running smoothly? Are there any problems with course materials or objectives? If yes, list any
changes/suggestions that you or your group members have to make the course better. What area needs
improvement and how do you suggest that it be done?
LIST PROBLEMS WORKED ON/CONCEPTS COVERED:
DID GROUP WORK OUTSIDE OF CLASS THIS WEEK:

if yes, list # of hours______
if no, what can be done to help the group meet outside of class?
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Teaching - Appendix C - Examples of QTL Communications:
QTL Meeting 1
I. Introductions:
II. Importance of Group Based Learning(GBL): Pharmacy classes currently using some form of GBL
are: OTC, Toxicology, Therapeutics, Pharmacokinetics, Pharmacology, Chemical Basis for Drug Action,
Parenterals and the list keeps growing… .. However, the main difference between the above classes and
this class is that we teach and monitor the group process along with the content. Past experience has found
that in group based learning, the content cannot be mastered if the group process is failing - course
performance is directly tied to group performance. Therefore, it is imperative that you learn principles of
group dynamics along with the course content. These skills will last you a lifetime and work in any group
situation you may find yourself. Remember as a future pharmacist, you will be a member of the health
care team - and it is necessary to work effectively with others (physicians, nurses, lab, x-ray, etc.) to solve
patient problems.
III. Peer assessment: In group based learning, you have an opportunity to observe your peers in a close
problem-solving environment. You will have more detailed insight and knowledge of their work than the
instructor. In order to honestly and effectively evaluate everyone’s performance within the group, peer
assessment is necessary. In your future as a pharmacist, you may be asked to fill out a performance
appraisal on a co-worker. Many pharmacists find this upsetting since they have had no prior experience at
doing this. We must get comfortable with the process of receiving and giving assessment feedback. In this
class, peer assessment will be worth 10% of your final exam grade. You will assess yourself and be
assessed by your peers at midterm and at the end of the course. Only the final peer and self assessment will
count towards your final grade. The mid-term assessment is for practice and your own personal growth.
See attached sample copy.
IV. Group dynamics - problems?
V. Decision making: Any group’s goal should be to reach a decision that best reflects the thinking of all
group members. This is called reaching a consensus. A consensus is finding a proposal acceptable enough
so that all members can support it and no member opposes it. A consensus is neither a unanimous vote - a
consensus may not represent everyone’s first priorities nor a majority vote - (in a majority vote, only the
majority gets something they are happy with; people in the minority get something they don’t want at all).
A consensus requires time, active participation of all group members, skills in communication (such as
listening, conflict resolution, and discussion), creative thinking and open-mindedness.
Rules for Decision by Consensus:
• Look for acceptable alternatives
• State your opinion - it doesn’t matter that others do not share it. Conflict spawns creativity.
• Look for win-win situations
• Remember that difference of opinion is healthy
Aiming for consensus requires a much different strategy than does unanimous or majority vote. To reach a
consensus, the group must let each member voice their concerns/opinions. It may be hard to tell when you
have reached consensus - a good rule of thumb is when no one is completely satisfied, but the decision is
one that you all can live with. Complete unanimity is not the goal - it is rarely achieved, but acceptance is.
VI. Time-lines:
How to deal with “floundering” (a lack of direction):
• Review the timeline within the group. Hopefully by this point you have set dates for exams and know
the topics to be covered for each. Draw the timeline out on paper. Give each member a copy. Assign
problems to individuals and keep track.
• State “Let’s review our timeline and make sure it is clear to everyone.”
• “What do we have to do next?”
• “What do we need to do/ask so we can move on? What is holding us up?”
• Finish up every class by giving everyone duties for the next meeting. There should not be any
confusion at that point as to who is responsible for what.
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Teaching Appendix D –
MID-SEMESTER PEER/SELF GROUP INTERACTION ASSESSMENT

Please evaluate each member of your calculations group and yourself. Evaluate performance over the first
half of the semester. You are expected to evaluate each member/self honestly. Please record your
evaluation responses below their names. Hand-written comments are encouraged. Turn in this sheet once
you have completed the evaluations. Be assured that your confidentiality will be maintained. You will get
a copy of these results along with any constructive hand-written comments.
Please indicate your response on the score sheet using the following rating guide.
The rating scale:
5 = Student is consistent and provides excellent contributions
4 = Student is generally consistent and provides very good contributions
3 = Student is somewhat consistent and provides satisfactory contributions
2 = Student is somewhat inconsistent and provides unsatisfactory contributions
1 = Student is inconsistent and provides inappropriate contributions (or doesn’t contribute at all)
Your name:_______________________ Section: _________ Group:__________
List group members below next to their suit:
Club:___________________________________
Diamond:________________________________
Heart:__________________________________
Spade:_________________________________
Extra:__________________________________
Supply written comments on back: General Group and Individual Group Members:
Assessment items Club Diamond Heart Spade extra

1. This person actively contributes to group discussions.
2. This person comes prepared for class each week.
3. This person helps to redirect discussions/problem-solving when

the group gets “off track.”
4. This person listens to the opinions and contributions of others.
5. This person exercises mutual respect for others in the group.

6. This person helps keep the group focused on the timeline.
7. This person works well with the other group members.
8. This person does not monopolize group discussions.
9. This person is available outside of class for group work.

10. This person shares their knowledge within the group.
25
Teaching Appendix E - MANAGING DIFFICULT PEOPLE
Just about everyone has felt the pulse-pounding, face-flushing, word-sputtering frustration caused by trying to reason with
difficult people. We find them to be uncooperative, uncompromising, and stubborn. Each encounter with them leaves us
feeling increasingly frustrated and angry. No matter what we do, it isn't effective. While it may seem easier to ignore
difficult people rather than face a confrontation, team morale and productivity greatly decrease when difficult people are
tolerated, even reluctantly. The following five strategies allow you to take control of situations involving difficult people and
build more cohesive teams as a result.
Question: can you find yourself - what type are you?
STRATEGY 1: De-personalize the situation
No matter how challenging, belligerent, or negative the difficult person behaves, do not take it personally. Difficult
people are often acting out their personal problems, and their behavior is a cry for help. You can more easily control your
emotional reactions to them and defuse any anger you feel if you do not take their behavior personally. When you
encounter a difficult person, observe how he or she behaves with others, especially other team members. You will find
that the behavior is consistently difficult. This awareness helps put things in perspective; you can see that you are not to
blame for the difficulty.
STRATEGY 2: Learn to identify difficult personalities
Generally, there are seven types of difficult personalities. As each type is presented, strategies for coaching, motivating,
and communicating with them will be presented. It takes some planning and practice, but as we learn to manage these
difficult types, the effectiveness of the entire team will increase.
ATTACKERS: Attackers are hostile, aggressive, abusive, and intimidating. They need to be right and will charge like
angry bulls if they think they have been challenged or crossed. The best coping strategy is to let them blow off steam and
express their anger in a safe environment. But you can't let them run on. To maintain control, address them by name:
“David, I hear what you are saying. Let's sit down and talk about it.”Getting attackers to sit will have a calming effect on
them; and, once calmed, attackers become more reasonable. Take what attackers say seriously. Hear them out, let them
know you have heard them, and then state your position clearly and avoid the temptation to argue.
EGOTISTS: Egotists are often experts and know more than others on the team about a particular subject. They believe
facts are power; and, since they know the facts, they act in a superior way that often demeans the knowledge of others.
Plan meetings so the egotists on the team speak first and allow time for them to “bask” in their knowledge. This strategy
minimizes their tendency to interrupt later in the meeting. You must be prepared with facts and information, because you
cannot “fake it” with egotists. But you can capitalize on what they know by asking questions. Egotists love to show off and
have their knowledge appreciated. If you approach them from this perspective, their abusive attitudes and behaviors can
be tempered so you can more effectively use their knowledge and expertise to support your efforts.
SNEAKS: Sneaks take potshots. They undercut your authority in devious ways by using sarcasm, which is often
disguised as a joke. Never ignore the sneak's snide comments. That just gives them power to continue Instead, expose
them. When they snipe at someone, be direct and ask them for their opinions or solutions. Force them into the open and
you will weaken their ability to cause problems. Try to turn their attention and comments to the issues, not the
personalities involved. Once they realize you won't put up with their sniping, they will stop.
VICTIMS: Victims see everything negatively. They complain, whine, seem to be powerless, and act defeated. Victims also
shift blame and refuse to take responsibility for situations or decisions, especially unpopular ones. They act as if they are
passing on orders from above and blame the boss for that “dumb” new policy. Such behavior hurts morale and erodes the
support of your team. Since victims often believe no one thinks they are important or takes them seriously, start your
interactions by listening to what they say. Steer them toward the facts, which are usually much less negative than their
interpretations. When you ask for suggestions to improve the situation, maintain control by bringing up the negatives
yourself, then dismiss each logically. Direct their attention to the more positive aspects of the situation.
NEGATORS: Victims seem pale compared to true negators. Negators aren’t just negative, they distrust anyone in power.
They believe that their way is the only right way, and their motto is “I told you so.”Stay positive, but realistic. Delay
discussing solutions, since negators will dismiss every solution as soon as it is spoken. Refuse to argue with them and
stick with the facts. Anticipate any objections they may raise and prepare facts and information to refute them.
SUPERAGREEABLE PEOPLE: While super-agreeable people are easy to like, they are one of the most difficult
personalities to deal with. Super-agreeables are outgoing and friendly; but, because they have such a strong need to be
liked, they frequently become whatever others need them to be at the expense of their own needs and desires. They are
usually terrified of making mistakes. Superagreeable people can’t say “No” and, thus, overcommit themselves and their
staffs. They disappoint and frustrate the very people from whom they so desperately need to receive approval— their
managers, staff, co-workers and, in personal matters, their family and friends. Carefully limit how much you ask of them to
eliminate the disappointments caused by missed deadlines.Teach them to see things in greater perspective to help them
overcome their fear of making mistakes.
26
UNRESPONSIVE PEOPLE: Unresponsive people are the ''clams'' of humankind. They are the most difficult personalities
to deal with. They don't reveal their true motives, and you play a guessing game trying to find out what makes them tick.
They are hard to understand and seemingly impossible to draw out. Yet that is the most effective strategy: draw them out.
Always ask open-ended questions that require more than “Yes” or “No” answers, then wait for them to respond. Typically,
they respond more slowly than other kinds of personalities and rely on others to take over so they can maintain their clam-
like reserves. Even if the silence between you and an unresponsive person grows chasmlike, wait for a response. If they
refuse to open up, agree to meet again later and ask them to think about specific topics you will discuss at that time. This
strategy will eventually draw them out-and, once they begin to trust you, they will become less clamlike.
STRATEGY 3: Characterize the difficult people in your life

No one demonstrates one of these personality traits to the exclusion of all the others. But most difficult people
demonstrate one so strongly, you can predict how they are going to respond. It is that predictability that gives you the
edge in any situation involving them because you can thoroughly prepare and practice how you will respond to their
behavior. And, as with anything else, practice makes perfect.
List the difficult people you work with and identify which personality most closely fits their dominant behaviors. Jot the
techniques for each personality on a 3 x 5 index card and review the cards before meeting with them. Take time to review
the strategies for dealing with a particular personality, and then recall a past unsatisfactory confrontation with him or her.
Imagine how much more successful it would have been if you had used the techniques for dealing with that personality.
Now, visualize your next confrontation with that person and see yourself Using these techniques. Rehearse until you feel
comfortable with the techniques and are well prepared to deal with the person who manifests this difficult personality trait.
STRATEGY 4: Encourage people to change

By becoming skillful in using these techniques, you will not only learn how to handle difficult people, you will be reinforcing
teamwork behaviors. When we ignore difficult people, they don't change. But when we insist they change, when we refuse
to indulge their behaviors, we require them to learn new coping skills. This can strengthen the entire team.
STRATEGY 5: Know when to give up

These strategies work with people who have grating personality traits, but you must be careful when working with people
for whom the strategies don't work. Keep in mind that some people may suffer from more than just difficult personality
traits. Some may have personal problems they cannot leave at home. If the strategies don't work, seek feedback from
someone who can recognize the existence of serious problems that need professional help. Always document facts about
incidents that occur and strategies you try with difficult employees. If leaders cannot control negative behavior, team
members lose respect for them. A highly cohesive team can soon become one with little cohesiveness and lower
productivity.
Dealing with difficult people doesn't have to lead to confrontation. It takes effort, time, and attention to turn a challenging
person into a productive and satisfying one. But when we are successful, our effectiveness and the effectiveness of the
teams we manage will improve and we will create win-win situations for everyone involved.
(Manning, Marilyn Ph.D. and P.A. Haddock. “Managing Difficult People,” SKY, November 1988, pp. 128-135)
27
F I R S T E D I T I O N
Basic Pharmacokinetics
Michael C. Makoid, Ph.D.

Professor of Pharmaceutical Sciences
Creighton University School of Pharmacy
and Allied Health Sciences,
Omaha, Nebraska
Phillip J. Vuchetich, Pharm.D.

Pharmacocybernetics Resident
Creighton University School of Pharmacy
and Allied Health Sciences,
Omaha, Nebraska
Umesh V. Banakar, Ph.D.

President, PharmAssist, Inc.
Indianapolis, IN
Basic Pharmacokinetics REV. 00.1.11 -1

Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/PHA443/pdf/
Copyright 1996-2000 The Virtual University Press
All rights reserved.
ISBN 0-000-000000-0
ABCDEFGHIJ-DO-89

Acknowledgement
When I first started teaching, I had the good fortune to work with another new
Ph.D., John Cobby. We struggled through our first five years on the otherside of
the podium together and learned many of the tenents upon which this book is
based, not content but process. First and formost, it was his belief that students are
bright, enthusiastic and hardworking. We should tell them what to do and get out
of their way. We both prepared extensive handouts complete with even more
extensive practice problems so that the student could experience the scientific
method as a detective might solve a murder mystery. The idea was to make learn-
ing pharmaceutical science interesting and fun. Through the years, as the methods
became more refined, student perceptions and performance improved dramatically.
John ultimately abandoned academe to go to work in the “real world” of industry,

clearly their gain and our loss. I approached him some years ago to co-author this
text. He declined believing himself to be too far removed from the cutting edge of
this discipline. That may be true (I doubt it!), but what can not be argued is that he
was a major contributor to this book in his philosophy and class notes. Over the
years, the explainations were rewritten and revised. Many new problems were
added and some were suplanted. These teaching aides have evolved but their ori-
gins are clear. Using the industry standard regarding authorship, which defines an
author as one whose contributions significantly alters the content of the paper, Dr.
Cobby is an author of this book.

CHAPTER 1 Introduction
Author: Michael Makoid and John Cobby

Reviewer: Phillip Vuchetich
OBJECTIVES
At the completion of this chapter, the successful student shall be able to:
1. define pharmacokinetics
2. state the overall objectives of the course
3. state the major themes of the course
4. state the course organizational structure with respect to study sections
5. state the objectives of each study section
6. state the examination structure and objectives
7. state student performance expectations
8. state the schedule and timeline
Basic Pharmacokinetics REV. 00.1.11 1-1

Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf/
Introduction
1.1 Basic Pharmacokinetics

What is pharmacokinet- Pharmacokinetics is the mathematics of the time course of Absorption, Distribu-
ics? tion, Metabolism, and Excretion (ADME) of drugs in the body. The biological,
physiological, and physicochemical factors which influence the transfer processes
of drugs in the body also influence the rate and extent of ADME of those drugs in
the body. In many cases, pharmacological action, as well as toxicological action, is
related to plasma concentration of drugs. Consequently, through the study of
pharmacokinetics, the pharmacist will be able to individualize therapy for the
patient.

Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
Introduction
1.2 Course Objectives:

The Roman numerals refer to the cognitive complexity as described in Bloom’s
Taxonomy of Educational Objectives described elsewhere in this document. At the
completion of this course, the successful student will be able to:
What will you be able to • Calculate (III) patient and drug specific pharmacokinetic parameters from patient data,
do? • Predict (calculate - III) the changes in relevant pharmacokinetic parameters in the patient with
selected diseases,
• Utilize the above parameters to individualize patient therapy (devise a dosage regimen - V),
• Communicate his/her therapy recommendations to another competent health professional (write
a consult - V).
1.2.1 COURSE ARRANGEMENT:

Two courses are described below. The first, a two credit (Creighton University
required) and the second, a three credit (CU optional) version. The two credit
course will consist of major themes one through three and exams one and two,
while the three credit course will add theme four and exam three. The four major
themes are entitled:
How is the course • Study Group 1: Learn the tools used by the discipline. Calculate patient and drug specific phar-
arranged? macokinetic parameters from single dose patient data,
• Study Group 2: Utilize the tools to optimize patient therapy under multiple dose conditions,
• Study group 3: Apply the tools to predict the changes in relevant pharmacokinetic parameters in
the compromised patient patient with selected diseases,
• Study group 4: Apply the tools in specialized drug classes.
Each major theme of the course is further broken down into study sections, each
with their own set of general objectives as shown below:

Introduction
1.2.2 STUDY GROUP 1: LEARN THE TOOLS USED BY THE DISCIPLINE.

CALCULATE PATIENT AND DRUG SPECIFIC PHARMACOKINETIC
PARAMETERS FROM SINGLE DOSE PATIENT DATA,
A. Basic Mathematical skills objectives:

What will I be required 1. Given a data set containing a pair of variables, the student will properly construct (III) var-
to be able to do? How ious graphs of the data.
will examination ques- 2. Given various graphical representations of data, the student will calculate (III) the slope
tions be written for this and intercept by hand as well as using linear regression.
material? 3. The student shall be able to interpret (V) the meaning of the slope and intercept for the
various types of data sets.
4. The student shall demonstrate (III) the proper procedures of mathematical and algebraic
manipulations.
5. The student shall demonstrate (III) the proper calculus procedures of integration and dif-
ferentiation.
6. The student shall demonstrate (III) the proper use of computers in graphical simulations
and problem solving.
7. Given the assumptions for the model, the student will construct (III) models of the ADME
processes using Laplace Transforms.
8. The student shall develop (V) integrated equations associated with the above models.
9. The student shall generate a pharmacokinetic model based on given information.
10. The student shall interpret a given model mathematically.
11. The student shall predict changes in the final result based on changes in variables through-
out the model.
B. Pharmacological Response objectives:

1. Given patient data of the following types, the student will be able to properly construct
(III) a graph and compute (III) the slope: response (R) vs. concentration (C), response (R)
vs. time (T), concentration (C) vs. time (T)
2. Given any two of the above data sets, the student will be able to compute (III) the slope of
the third.
C. IV one compartment model, plasma and urine objectives:

1. Given patient drug concentration and/or amount vs. time profiles, the student will calcu-
late (III) the relevant pharmacokinetic parameters available ( V d , K, k m , k r , AUC , Clear-
ance, MRT) from IV data.
2. Given the appropriate pharmacokinetic parameters, the student shall simulate (III)
I.V. bolus/infusion dosing for parent compounds
Plasma concentration vs. time profile analysis
Rate vs. time profile analysis
3. Given patient specific pharmacokinetic parameters, the student shall provide professional
communication regarding IV bolus/infusion information
4. The student shall utilize computer aided instruction and simulation
5. Given patient drug concentration and/or amount vs. time profiles, the student will calcu-
late (III) the relevant metabolite (active vs. inactive) pharmacokinetic parameters avail-
able ( V d , K, k m , k r , AUC , Clearance, MRT) from IV data.

Introduction
D. Biopharmaceutical factor objectives: the student shall be able to discuss:

1. physiology and mechanisms of absorption
2. effects of diffusion, cardiac output / blood perfusion, physical properties of the drug and
body on distribution
3. biotransformation, first pass effect, and clearance
4. renal, biliary, mammary, salivary, other forms of excretion.
5. the effects of physiological changes with age, sex, and disease on the absorption, distribu-
tion, metabolism, and excretion of a drug.
E. Oral one compartment model objectives:

1. Given patient drug concentration and/or amount vs. Time profiles, the student will calcu-
late (III) the relevant pharmacokinetic parameters ( V d , K, k m , k r , k a , AUC , Clearance,
MRT, MAT) available from oral data.
F. Bioavailability objectives:
1. Given sufficient data to compare an oral product with another oral product or an IV prod-
uct, the student will estimate (III) the bioavailability (compare AUCs) and judge (VI) pro-
fessional acceptance of the product with regard to bioequivalence (evaluate (VI) AUC, T p
and ( C p )max ).
2. The student will write (V) a professional consult using the above calculations.
1.2.3 STUDY GROUP 2: UTILIZE THE TOOLS TO OPTIMIZE PATIENT

THERAPY UNDER MULTIPLE DOSE CONDITIONS,
G. Dosage regimens objectives:

1. Given population average patient data, the student will devise (V) dosage regimens which
will maintain plasma concentrations of drug within the therapeutic range.
2. Given specific patient information, the patient will justify (VI) dosage regimen recom-
mendations.
3. Given patient information regarding organ function, the student will devise (V) and justify
(VI) dosage regimen recommendations for the compromised patient.
4. The student will write (V) a professional consult using the above calculations
1.2.4 STUDY GROUP 3: APPLY THE TOOLS TO PREDICT THE CHANGES IN

RELEVANT PHARMACOKINETIC PARAMETERS IN THE
COMPROMISED PATIENT PATIENT WITH SELECTED DISEASES,
H. Clearance objectives:
1. Given patient information regarding organ function, the student will calculate (III)
changes in clearance and other pharmacokinetic parameters inherent in compromised
patients.

Introduction
1.2.5 STUDY GROUP 4: APPLY THE TOOLS IN SPECIALIZED DRUG

CLASSES.
I. Two Compartment Model objectives:

1. Given patient Concentration and/or Amount of Drug vs. Time, profiles the student will
calculate (III) the relevant pharmacokinetic parameters( V d1 , Alpha, A 1 , Beta, B 1 ,
k 10 , k 12 , k 21 , AUC , Clearance, compartmental amount ratios) available from two com-
partment data.
2. Given population average patient data, the student will devise (V) a dosage regimen which
3. Given specific patient information, the patient will justify (VI) the optimal dosage regi-
men.
(VI) the optimal dosage regimen for the compromised patient.
J. Non-linear kinetics objective:

1. Given population average patient data, the student will devise (V) a dosage regimen which
2. Given specific patient information, the patient will justify (VI) the optimal dosage regi-
men.
(VI) dosage regimens for the compromised patient.

Introduction
1.3 Exams
How are the exams Exams will consist of problems which will be linked directly back to an objective
made? (above) and a library assignment in which you will be asked to evaluate a research
article with the tools available to you by the time of the exam as discussed below.

Introduction
1.3.1 LIBRARY ASSIGNMENT IN PHARMACOKINETICS
K. Library Assignment Objectives

What do I have to do in 1. Given a suitable primary research article in the area of pharmacokinetics, the student shall
the library? calculate the pharmacokinetic parameters from the data using the tools learned in class
both by hand and utilizing the computer program, PK Solutions.
2. The student shall communicate in writing the results of such calculations with suitable
commentary regarding differences and interpretations.
Format of the “paper”:

How should the paper 1. Tell me what type of paper you have chosen to evaluate:
look?
The problem sets show what data you need for each of these.
First Exam
What content should I IV Bolus Parent compound 50 pts
look for in the paper and IV Bolus Parent metabolite 65 pts
what is its relative
IV Infusion 65 pts
worth?
Pharmacological Response 75 pts
Oral Dosing / Bioavailability 50 pts
Second Exam (Pharm.D. course)

Multiple dosing 50 pts
Clearance and disease 60 pts
Dosage Regimen 75 pts
Third Exam (Masters / Honors course)

Two compartment model 50 pts
Protein Binding and Disease 65 pts
Non-linear kinetics and disease 75 pts
2. Include a Xerox copy of the entire paper. I need to evaluate it, too.
3. Enlarge the graph by successive Xeroxes so that you can accurately evalu-
ate the data.
4. Do analysis of data by hand and by PK Solutions.
5. Compare your work with the author’s (short paragraph).

Introduction
6. Comment on any differences of parameter calculation or interpretation. See

objectives above (Paragraph).
7. Write an exam question to obtain pharmacokinetic parameters. You know

from the first exam what they should look like.
Why do I need to do this Each of the above sections is designed to bring the student an understanding of the
library assignment? information and the processes necessary to operate as a competent professional in
the area of pharmacokinetic evaluation and consulting. Consequently, the
course will evolve from a quantitative, manipulative mathematics course to a
course which stresses communication skills. Consults will be graded not only on
content (the proper dosage regimen for the patient) but also grammar, punctuation,
spelling, organization and neatness. You may have the best medical information in
the world, but if it is poorly executed, it will be ignored.
Can I cram the night This course will probably be one of the more rigorous ones that you will have
before? experienced in your college career to date. It will be one of the first ones which
attempt to show some clinical relevance. The course can be successfully com-
pleted with your current skills and background. It is not difficult IF (and that is a
big IF) taken slowly, in small bites. Its just like eating an elephant - you can’t do it
all in one sitting. Some of you may try to get it all the night before the exam,
regardless of my admonitions and those of your upper-class friends (ask them!). In
many cases, that has been more than sufficient to get A’s and B’s on exams in pre-
vious courses. Past experience tells many of you that you can do it. I suggest that
the requirements and expectations of a professional school are considerably more
than your undergraduate experience and it most likely will not work in many
courses which require assimilation of the information presented, as is expected in a
professional program.

Introduction
1.4 Blooms taxonomy for the Hierarchy of Educational Objectives

Blooms taxonomy for the Hierarchy of Educational Objectives describes the
expectations of a course in increasing order of complexity as:
What is cramming good I. To Know: means to memorize (recognize, recall) (Many college courses
for? Lowest level of cog- require only this level of cognitive effort, hence the extensive experience with
nitive skills. “multiple guess” exams).
II. To Comprehend: means to translate; to be able to put information into your

own words. (Essay exams routinely call for this level of effort on the part of the
student).
This is where we begin. III. To Apply: means to be able to use knowledge, rules and principles in an
unfamiliar situation. (This is the lowest level of skill necessary to function at a
technician level).
This is where we need IV. To Analyze: means to be able to critically examine a body of knowledge
to be in school. and to be able to identify the relationships. (This is where a B.S. graduate should
operate. Education obviates the need for teachers.)
This is where we need V. To Synthesize: means to put together information, not necessarily previ-
to be as graduates. ously so organized, in order to get a new piece of information. (This is the begin-
ning level of professional judgment).
VI. To Evaluate: means to be able to judge the worth of an idea, form hypothe-
ses and do problem solving, research, invent new knowledge. (This is the doctoral
level of participation in the area).
Can’t I just do it the A professional routinely operates at level IV and V with occasional forays into
same way that I have level VI. This is where you will operate in this course and in most subsequent
always studied? courses in the professional curriculum. You will note that each of the objectives for
the course contains specific action words followed by the level in the taxonomy at
which you will operate. These are the standard descriptive terms for use in instruc-
tional objectives. You will be asked to do critical thinking, not simply recite or
recognize the right answer. Problems challenge thinking skills and demand the
synthesis of material into concepts. To facilitate this transition we both must work
very hard.

Introduction
1.5 Course Contract

I Will:
What will the teacher do 1. Provide individualized learning methods: Some students learn by hearing
in this class? Act as a and others by seeing (auditory or visual learners). I have designed the course to
facilitator. accommodate both types of learners. In class, I will provide you with executive
summaries of what you read. I will provide group leaders with detailed reviews of
materials for which they are responsible. I will tell you what I’m going to say, say
it, and then tell you what I said. I will also attempt to write it out and draw appro-
priate graphs, charts and pictures as well as appropriate visual aids in class and
with the homework problems. I will provide you with ample examples of the types
of manipulations that you will be expected to do. I will provide you with ample
problem sets so that you may practice those manipulations. I will provide you
with computer simulations so that you may see these manipulations in action and
begin to get a feel for the numbers and their magnitude. Feedback and interaction
is encouraged. If I am not meeting your perceived needs, you must tell me. Some
students might feel too intimidated to ask questions. To obviate this problem, you
will elect a group team leader, an ombudsman, whose job it will be to carry your
questions, concerns, and comments to me. It is your job and his responsibility to
see that the group interaction facilitates the learning process. This is not to prevent
you coming to see me but offered as another avenue of communication.
Will I learn anything rel- 2. Provide clinical relevance to the practice of pharmacy. This will be stressed
evant in this course? at all times. I will also relate real clinical experiences; virtually all of the problems
come from real patients. Some educators believe examples must fit the theory
exactly. This gives the student a false set of reality parameters. Consequently,
when “the data does not fall on the line” the student rejects relevant information.
You will become familiar with real data, and the problems associated with real
data.
How will I know how I’m 3. Give adequate feedback: Evaluation of your performance will be available
doing? to you at all times. A running evaluation, updated weekly will be on my door for
your review. You may check any thing with me at any time. I expect that you will
see me outside of class time either individually if you need help or in supervised
review sessions. You must see me for assistance if your performance is unsatis-
factory.
What will the teacher be 4. Teach: As an operational definition this means: clarifying what you read,
doing? Engaging you in demonstrating how and why things work as they do, and unifying the material -
an active learning pro- attempting to generate the A - HA! syndrome. The correlate of teach from the stu-
cess.
dent view is learn. Neither is a passive process. I can not open your head and pour
the knowledge in. A saying in education is: “Knowledge maketh a bloody
entrance”. You must expend the effort necessary for you to learn.

Introduction
What must I do in this 5. Facilitate Learning. You received objectives (above) and a summary for
active learning process? each study section (chapters in this text), of exactly what is expected of you with
You MUST participate in examples in the problem sets at the end of each chapter. We will have ample time
class and in your
assigned groups!!!
during class to field questions generated by the correlated reading and problem
sets, as well as homework assignments. I will not be duplicating any book’s efforts.
Student participation in class is required. You will answer (as well as ask) ques-
tions, do problems in class. You will sound things out and get feedback from me
and your fellow colleagues. Remember - the class is to help you learn. It is not the
sole means of learning, nor am I the source of all knowledge. Its’ only reason for
being is to help you organize and summarize what you learn. It has a relatively
simple plan with multiple examples. From these examples you will develop con-
cepts which will obviate the need for memorizing individual facts (or actually me
entirely). I will assist you in the formation of these concepts. It is patently obvious
that I can not give you every possible example of every type of question that you
will be asked during your professional career. For one thing I don't know what
questions you will be asked nor problems you will encounter. Going from the spe-
cific to the general forms concepts which will allow you to go from the general to
the specific, even if you have never been there before. The total medical knowl-
edge is now doubling at a rate of every 4 years. I can not teach you the content nec-
essary to operate 5 years in the future, let alone 40. You must learn to learn.
Hence, if you plan to become a competent professional, you must operate at least
in Bloom's level V.
How do I get in touch 6. Be available: I do not have office hours. I believe them to be restrictive
with the teacher? from your view point. What I do have is a schedule calandar preparede weeks in
advance of when I am NOT available. You may set an appointment, at least a 1/2
day in advance to guarantee that I see it, any other time. Of course, appointments
are not necessary if I'm in my office, but you take the chance of my not being there
or someone else being there ahead of you if you do not sign up. You may contact
me by e-mail: makoid@creighton.edu, or by phone: 402-280-2952. You may also-
contact my secretary, Dawn Trojanowski in the departmental office or by phone
402-280-2893 to make an appointment.
How can I tell the 7. Be responsive: Each day, you will be asked to provide me with a one
teacher how things are minute summary of the topic consisting answering the following questions:
going?
a. What was the main thrust of the study section (What did you read)?
b. What was clear about the study section? What was done well?
c. What was unclear? How could it be done better?
This will provide me with a running monitor of my effectiveness as well as a

framework of what to stress and what to change.

Introduction
Do I have any say in the After each exam, in addition to working out the problems, we will decide whether
examination questions? any individual question was not covered by the objectives. Note: Not that it was
tough, not that you got it wrong, not that it didn’t allow you to tell me what you
knew, but did I tell you that I was going to ask you to do it? (Was it covered by the
objectives?)
How are the exams 8) Evaluate your performance fairly and honestly: Quite simply, I’m going to tell
graded? you what I expect that you will do. I will show you how to do it. I will provide you
with practice in doing it. I will provide you with an exam which tests your ability
to do it. The exams, as well as the whole course, will use real data and/or pharma-
cokinetic parameters for real drugs in real patient settings, much like the state
board exams (and hopefully real life). Like both of these situations, all answers are
interconnected. What that means is, if you improperly calculate a parameter which
is needed to make another calculation which is used to make a third, etc. ALL are
wrong. Conversely, if you can’t get a particular calculation by one method or equa-
tion, try another. That’s simply the way it is. You probably wouldn’t get much sym-
pathy if you calculated a dosage regimen properly based on a wrong elimination
rate constant and ended up killing your patient.
You Will:
What do I have to do? 1) Come prepared to participate in class. This is your full time job. If you are
How much work is really working full time, it is usually 40 to 60 hours per week. If you go to college 15 to
expected? 18 credits and prepare/study 2 hours for each credit, you work 45 to 55 hour per
week - you have a full time job. Your commitment is the 45 to 50 hour week not
just the contact hours and a night for each exam. This specifically means for each 1
hour class, I expect no less than 2 hours of preparation on your part. Each of you
will be assigned to a study group. You will work the problems together and teach
each other both in and out of class. We will have group discussion of class as well
as group problem solving. It will be your responsibility that every member of
your group be adequately prepared to answer for the group during recitation. There
will be a grade for group participation. Part of your grade will be based on your
peer evaluation.
Do I have to read the 2) Read the text. When you read, read critically. Do you understand each idea?
text? Each page in the HTML version has an evaluation section. If you get it you will be
asked to be a resource for that page for your peers. If you don’t get it, you will be
directed to your peers to seek help. Come prepared to ask about it in class.
Why do I have to do the 3) Work the problems. Check the answers. These come from old exams, so they
problem sets? are the type that you are likely to see. Work them in your study groups so that
everyone can see your thought processes. Bring them to class if you can not do
them or come and see me privately. Be prepared to show me your attempts at solv-
ing the problem. I will show you how to get started and give direction to your
thought. I will not work the problem for you. You would not learn if I did it for
you. It is crucial that you work the problems. Each has a specific objective. Over-

Introduction
all, they contribute to your gaining facility in the processes that a pharmacokineti-
cist must know how to do.
Can I just coast 4) Do not delude yourself with respect to your performance. If you received a
through? grade that was less than satisfactory for you, do not simply console yourself by
saying “I knew the stuff, I just made a little error.” Can you get it right consis-
tently? That's when you know the stuff. That is not a laudable goal. That's what a
professional does. There have been several students in the past that “knew that
stuff” right up till the time that they had to repeat the course (and sometimes
beyond).

Introduction
1.6 Computers in the course

Can I get through with Computer literacy is necessary in this field. Consequently computers will pervade
just paper and pencil? the course. The homework problems (above) are to done both by hand and
checked with the computer. This will help your understanding of pharmacokinetics
in general and that homework objective in particular. Computers are natural
adjunctive tools in the teaching of pharmacokinetics. The are able to simulate the
concentration vs. time profiles and do difficult repetitive calculations which allow
the student to get a broad view of the processes involved.
What are the programs Program that is becomming the industry standard and is currently being used in the
that I will be using? course is PK Solutions. We have a site licence for it and a working copy is in the
computer lab. It is a required text for the course. You will need to learn to use the
software as complete instructions are available with its purchase.
In addition to the above course objectives, there are specific objectives for the use
of computers in the course. They are:
What will I be expected • Simulation. The student will be able to utilize appropriate graphs and histograms used classical
to do with the comput- pharmacokinetics in the course. The student will demonstrate effects of changes in pharmacoki-
ers? netic parameters on the ADME processes and correlated pharmacological / therapeutic
response.
• Graphical Solutions. Many thing become more understandable in graphical form, or at least we
are able to predict what would happen if a trend were to continue.
• Numerical solutions. The computer would accurately and repeatedly calculate convoluted, diffi-
cult equations quickly and easily.
These objectives will be met in a variety of ways. Clearly, the most direct method
is the solution of the problem sets by computer. First, I expect that you would do
the problem by hand, complete with graphs and other supporting calculations fol-
lowed by computer simulation and data analysis. Just how close did you come to
the best fit? Next, a portion of each exam will be a library exercise in which you
will find and evaluate a published article according to the principles that you
learned in class utilizing the computer facilities. How close did you come the
authors numbers? Do you, in fact, even agree with the authors? You will prepare a
short consult in which you describe the patient and what the authors did along with
your support (or non-support) of the authors conclusions.

Introduction
1.7 Survival Kit
1.7.1 THINGS FOR YOUR SURVIVAL KIT!

x
What do I need to buy 1. You will need a good calculator - One with e and ln x functions. You must
RIGHT NOW? have it ASAP. You will use it in class.
2. You will also need 2 cycle semilog paper and a clear straight edge ruler for
use in class. These are available in the book store or at an office supply store. You
can also downoad a copy of graph paper printer for you own personal use. A copy
is available in the computer lab.
3. You will need access to a pentium computer. The software, PK Solutions,

is pre-loaded in the Criss computer lab. Purchase is required for home use.
4. You will need a 3” D three-ring binder for collecting and maintaining all
the pages in this book as well as your class notes.
What do I need to do in Work in your study groups. You never learn it so well as when you teach it to
and out of class? someone else. Everyone benefits from a well run prepared study group. You are
not in competition with your fellow classmates. If everyone earns an “A”, then
everyone will receive one.
How can I organize this Organize and label your study notes. This is basic survival. This is one strategy
material? that I find works well. I recommend it highly. Good study notes are formatted on
loose-leaf in a three ring binder. The individual pages have a line drawn down
about 1/3 the way in. The notes are taken on the right (2/3) of the page, while
labels go in the left. The labels on the left are often written as questions, which are
answered in the text on the right. Loose leaf binders allow for the incorporation of
reading summaries as well as relevant problems and homework to be organized
with a divider all in one place. You should write intelligently, with proper punctua-
tion and spelling as if you were preparing a consult for a physician. Organization is
the key.
Remember: you may have all the information in the world at your fingertips; be
able to solve the most difficult therapy problem and no one will listen to you if you
can't communicate intelligently. You will be required to communicate in this
course utilizing both written and verbal skills.
Chapters in the book will be organized as above.

Introduction
1.7.2 WHAT YOU WILL GAIN: (YOUR GOALS)

How is the course to be 1. At the lowest level, a decent grade for a significant course. Specific grades
graded? will be earned by attaining the following points:
• A 900 and above
• B+ 850 to 899
• B 800 to 849
• C+ 750 to 799
• C 700 to 749
• D 600 to 699
• F 599 and below
Points in the course are assigned for various activities:
TABLE 4-1
Exam 1 410
Exam 1 grp/ind 40
Library 1 50-75
Exam 2 410
Exam 2 grp/ind 40
Library 2 50 to 75
Total 1000 to 1050
Group Bonus -50 to +50
Group Total 950 to 1100
You will be require to pass the first exam before you are allowed to take the
second.
2. At the next higher level, I will guarantee that if you comprehend this mate-
rial at level V, you will have no trouble passing any state board anywhere with
regard to pharmacokinetics.
3. You will gain a useful skill that will make you an integral part of the health
care team.
Do I really need a 4 You will learn to learn. There is an old proverb which goes: “Give a man a
teacher to learn? fish and you feed him for a day. Teach a man to fish and you feed him for a life-
time.” The B.S. Degree is designed to eliminate teachers. An educated man is one
who has learned to how to learn, not one who memorized a page in a book. That
is what you need to be a professional. The total medical knowledge is doubling at a
rate of every 3-4 years. That means that you will be out of date shortly after gradu-
ation (if not before) if you simply memorized content and don't learn to learn and
continue to learn throughout your career.

Introduction
What about cheating? One last piece of information: Neither you nor I will not tolerate any academic
misconduct. Anyone caught will minimally receive an “F” for their efforts and I
will recommend dismissal from the program. The profession has no room for
unprofessional behavior. I will prosecute.

Introduction
1.8 Tentative Schedule
1.8.1 STUDY GROUP 1: LEARN THE TOOLS USED BY THE DISCIPLINE.

CALCULATE PATIENT AND DRUG SPECIFIC PHARMACOKINETIC
PARAMETERS FROM SINGLE DOSE PATIENT DATA,
A: Introduction
1. Texts
2. Literature
3. Grading Policy
4. Course Philosophy
B: Math review
1. Numbers and exponents
2. Graphs and reaction order
3. Calculus
4. Laplace transform
5. Computer Introduction
6. Computer simulation and problem sets
C: Pharmacokinetic modeling
1. What a model is and what it isn’t.
2. Why we model
3. Philosophy of modeling
D: Pharmacological Response
1. Michaelis - Menton Mass balance equation
2. Interrelationships between Concentration, time and response.
E: I.V. Bolus dosing

1. Parent compound
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II Urine
a. Amount vs. time profile analysis
b. Rate vs. time profile analysis
c. Computer aided instruction and simulation
d. Problem sets

Introduction
e. Professional communication.
2. Metabolite
I. Plasma
c. Problem sets
II. Urine
a. Rate vs. time profile analysis
c. Problem sets
F: I.V. infusion
1. Parent compound
I. Plasma
c. Problem sets
II. Urine
d. Problem sets
1. Metabolite
I. Plasma
c. Problem sets
II. Urine
d. Problem sets
G: Biopharmaceutical factors
1. Absorption
I. Physiology
II. Mechanisms

Introduction
III. Physiological changes with age, sex, disease

2. Distribution
I. Diffusion
II. Cardiac output / blood perfusion
III. Physical properties of the drug
IV. Physical properties of the body
V. Physiological changes with age, sex, disease
3. Metabolism
I. Biotransformation methods
II. First pass effect
III. Clearance
IV. Physiological changes with age, sex, disease
4. Excretion
I. Renal
II. Biliary
III. Mammary
IV. Salivary
V. Misc.
VI. Physiological changes with age, sex, disease
H: Oral dosing
1. Parent compound
I. Plasma
c. Problem sets
II. Urine
d. Problem sets
2. Metabolite
I. Plasma
c. Problem sets
II. Urine

Introduction
d. Problem sets
I: Bioavailability, Bioequivalence, Drug product selection
1. Relative and Absolute Bioavailability
2. Factors Influencing Bioavailability
3. Methods of Assessing Bioavailability
I. in vivo
II. in vitro
III. Correlation
4. Bioequivalence
5. Bioavailability
6. Drug Product Selection
1.8.2 STUDY GROUP 2: UTILIZE THE TOOLS TO OPTIMIZE PATIENT

THERAPY UNDER MULTIPLE DOSE CONDITIONS,
J: Dosage regimen (Healthy, aged and diseased patients)
1. Multiple dose kinetics
2. Optimization of dosage regimen
3. Computer aided instruction
5. Computer aided consultation
6. Professional consultation process
1.8.3 STUDY GROUP 3: APPLY THE TOOLS TO PREDICT THE CHANGES IN

RELEVANT PHARMACOKINETIC PARAMETERS IN THE
COMPROMISED PATIENT PATIENT WITH SELECTED DISEASES,
L. Clearance objectives:
changes in clearance and other pharmacokinetic parameters inherent in compromised
patients.
1.8.4 STUDY GROUP 4: APPLY THE TOOLS IN SPECIAL CASES.

K: Multicompartment Modeling
1. Parent compound plasma vs. time profile analysis
2. Multiple dose considerations

Introduction

L: Protein Binding (healthy, aged and diseased patients)
1. Mass balance considerations / drug interactions
2. Effects of protein binding on pharmacokinetic parameters
M: Non - linear (Michaelis - Menton) kinetics
End of material for Masters / Honors course

Introduction
1.9 Competency Statements Related To Pharmacokinetics

The profession of pharmacy has determined that there are minimum, entry level
abilities necessary for a pharmacist. These form the Standards of Practice for the
profession of pharmacy, as written by The National Association of Boards of Phar-
macy (who make the NABPLEX, coincidentally). It is important to note that these
abilities are not thought up by some faculty member who sits in his ivory tower
saying what he thinks is important. These are what pharmacists do. They have
been promulgated as competency statements They are also the basis for the state
board exams as well as the basis far your coursework while in the School of Phar-
macy. They are broken down into five general areas:
1.00.00 Interpreting and dispensing prescriptions/ medication orders,
2.00.00 Assessing prescriptions/ medication orders and the drugs used in dispensing them,
3.00.00 Compounding and calculations involved in extemporaneous preparation of prescriptions/ medication

orders,
4.00.00 Monitoring drug therapy,
5.00.00 Counseling patients and health professionals.
For a complete listing of competency statements please refer to the NABPLEX

Candidate’s Review Guide, published by the National Association of Boards of
Pharmacy.
1.9.1 SPECIFIC COMPETENCY STATEMENTS ADDRESSED IN THIS

COURSE
1.00.00 Interpreting and Dispensing Prescriptions/ Medication Orders
1.04.00Given a prescription or medication order, the candidate shall identify or explain the rationale for the
dosage regimen.
1.04.03The candidate shall calculate the dose or rate of administration of a drug when given appropriate data.
2.00.00 Assessing Prescriptions/Medication Orders and the Drugs Used in Dispensing Them
2.01.00 The candidate shall identify, interpret, or explain patient or pharmacokinetic factors that affect either the
efficacy or safety of individual drug therapy.
2.01.01The candidate shall relate the influence of patient factors (e.g., age, weight, sex, occupation, compli-
ance, exercise, stress, placebo effect, vital organ function) to the choice or dosage of drug therapy.
2.01.02 The candidate shall explain or apply biopharmaceutical principles or pharmacokinetic factors (e.g.,
absorption, distribution, metabolism, excretion) as they relate to dosage regimen design or evaluation of experi-
mental or patient data, including the: definition or explanation of biopharmaceutical terminology; recognition of
the effects of patient health status or concurrent drug therapy on bioavailability; determination of pharmacokinetic
parameters or dosing regimens (e.g., loading dose estimations, maintenance dose calculation, elimination half-

Introduction
life, determinations of clearance, or volume of distribution); or recognition of biosocial factors that affect pharma-
cokinetic parameters (e.g., smoking, alcohol consumption, work environment.
2.03.00 Given appropriate information or data regarding bioavailability, the candidate shall demonstrate proper
judgment to assure safe and effective drug therapy.
2.03.01The candidate shall interpret or utilize in vitro dissolution test results that are used to predict bioequiv-
alence or shall distinguish these from in vivo tests.
2.03.02 The candidate shall differentiate between relative and absolute bioavailability.
2.03.03 The candidate shall interpret area under plasma concentration versus time curves as an assessment
of bioavailability.
2.03.04 The candidate shall explain or interpret the effect of rate of absorbtion on maximum plasma concentra-
tions and times of maximum plasma concentrations after drug administration.
2.04.00 The candidate shall identify, interpret, or evaluate sources of information for clarifying or answering
questions related to prescriptions, medication orders, or health care.
2.04.01 The candidate shall select appropriate books or references containing needed information (e.g.,
bioequivalence, incompatibility, drugs for emergency situations, physicochemical stability).
2.04.02 The candidate shall evaluate the suitability, accuracy, or reliability of information (e.g., pharmacokinetic
characteristics untoward effects, therapeutic efficacy) from literature sources.
4.00.00 Monitoring Drug Therapy
4.01.02 The candidate shall identify, collect, or evaluate patient information that relates to the effectiveness of
drug therapy (e.g., clinical observations, pharmacokinetic data, laboratory test results, sensitivities).
5.00.00 Counseling Patients and Health Professionals
5.01.00 The candidate shall counsel a patient or health professional regarding the indications, benefits, admin-
istration, storage, or untoward effects of prescription medications.
5.01.01 The candidate shall explain the proper procedure for taking or administering the drug (e.g., dosage,
time of day, method or time of administration -- before or after meals, duration of use), or for providing auxiliary
instructions about the medication.
5.01.03 The candidate shall explain cautions regarding food, drugs, chemicals, or nutrients that should be
avoided while particular medications are taken.
5.05.00 The candidate shall advise consumers regarding the selection, proper use, effects, precautions, or
contraindications of OTC products.
5.05.03 The candidate shall explain how a drug is to be taken (e.g., dosage, time of day, frequency, before or
after meals).

Introduction
1.10 Pharmacokinetic Symbolism

Pharmacokinetics was developed in several locations simultaneously. Because of
this, the symbols used in the literature are not consistent. Provided each symbol is
rigorously defined prior to use, this inconsistency should not prove an insurmount-
able difficulty when assessing the literature. In this book, the symbolism below
will be generally used, though, as an illustration of the variety, some deviation may
be anticipated on occasions.
1.10.1 AMOUNT TERMS (UNIT: MASS)
ARE amount remaining to be eliminated (excreted)
D dose (or maintenance dose)
DL loading dose
Xa amount of drug remaining to be absorbed at any time
X amount of unchanged drug in body at any time
Xm amount of metabolite in body at any time
Xu cumulative amount of unchanged drug excreted into urine up to any time
X mu cumulative amount of metabolite excreted into urine up to any time
X max maximum amount of unchanged drug in body
X min minimum amount of unchanged drug in body
X average amount of unchanged drug in body (also Laplace transform)
X eff minimum amount of unchanged drug in body necessary for pharmacologi-

cal response

Introduction
1.10.2 CONCENTRATION TERMS (UNITS MASS/VOLUME)
Cb concentration of drug in blood at any time
Cp concentration of drug in plasma at any time
Cm Concentration of metabolite in plasma (or blood) at any time
ss
(Cp ) “average” steady-state concentration of drug in plasma during a dosing
avg
interval
ss
(Cp ) maximum concentration of drug in plasma
max
ss
(Cp ) minimum concentration of drug in plasma
min
Cp average concentration of drug in plasma
KA dissociation constant of drug-protein complex
KM Michaelis-Menton rate constant
KR dissociation constant of drug-receptor complex
MEC minimum effective concentration of drug or metabolite
MTC minimum toxic concentration of drug or metabolite

Introduction
1.10.3 VOLUME TERMS (UNIT: VOLUME)
Vd apparent volume of unchanged drug distribution in compartment
Vm apparent volume of metabolite distribution in compartment
Vw physiological volume of plasma water
1.10.4 TIME TERMS (UNIT: TIME)
t time since administration of dose
T duration of zero-order input
t' time since cessation of zero-order input
t0 lag time
t mean time during sampling interval
t½ elimination half-life (“biological half-life”)
t 0.5 time for 50% removal
t max time when maximum amount or concentration occurs
t dur duration of effective pharmacological response
τ dosing interval (greek theta)
b time variable used in association with zero-order input

Introduction
1.10.5 RATE CONSTANT TERMS (UNIT: RECIPROCAL TIME (*), MASS/TIME

(**))
K, ke ,K i , apparent first-order rate constant for elimination, Summation of all the

ways the drug is eliminated (*)
ka apparent first-order rate constant for absorption (*)
k u, k r apparent first-order rate constant for urinary (renal) excretion of unchanged

drug (*)
km apparent first-order rate constant for metabolism of unchanged drug (*)
k mu apparent first-order rate constant for excretion of metabolite (*)
k ij apparent first-order transfer rate constant (*)
k0 zero-order input rate constant (**)
Q zero-order infusion rate constant (**)
R rate constant for decline in pharmacological effect (usual units:%/time)
α hybrid first-order rate constant (*) (greek alpha)
β hybrid first-order rate constant (*) (greek beta)

Introduction
1.10.6 CLEARANCE TERMS (UNITS: VOLUME/TIME)
Cl total body clearance (TBC)
Cl r renal clearance (RC)
Cl m metabolic clearance (MC)
Cl cr creatinine clearance
Cl H hepatic clearance (HC)
1.10.7 RATE TERMS (UNITS: MASS/TIME (*), MASS/TIME, VOLUME (**),

VOLUME/TIME (***)
dX
------- instantaneous rate of change of amount of unchanged drug (*)
dt
X
---- measured rate of change of amount of unchanged drug (*)
t
RH rate of plasma flow through the liver (***)
Rr rate of plasma flow through the kidney (***)
VM theoretical maximum rate of a process (**)
1.10.8 OTHER TERMS
AUC area under the plasma concentration-time curve (units: time * mass/vol-
ume)
AUMC area under the first moment of the plasma concentration-time curve (units:
2
time ⋅ mass ⁄ volume )
MRT Mean Residence Time (units: time )

Introduction
MAT Mean Absorption Time (units: time )
MDT Mean Dissolution Time (units: time )
E intensity of pharmacological effect
EH steady-state hepatic extraction ratio
Er steady-state renal extraction ratio
E max maximum intensity of pharmacological effect
F fraction of administered dose ultimately absorbed
FRE fraction remaining to be eliminated (excreted)
H hematocrit (fractional volume of erythrocytes in whole blood)
N number of elimination half-lives in a dosing interval
R accumulation factor
b intercept
f fraction of drug that is free (unbound)
f ss fraction of steady-state
m slope (sometimes specifically for log dose-response plot)
n number of doses
s Laplace operator
[ ] indicates molar concentration

Introduction
1.10.9 SUBSCRIPTS
0 at time zero
∞ at time infinity
ss during steady-state
t at time t
T at time T
n following dose n
diff difference between extrapolated and observed
int intrinsic
i index (i.e., 1,2,3)
j index (i.e., 1,2,3)
1.10.10 SUPERSCRIPTS
x extrapolated
x° last measured value

Introduction
1.11 First Lesson in Pharmacokinetics

It should be intuitively obvious to the most casual observer that the relative bio-
availability of 2 simultaneous I.V. bolus doses of a drug is equal to the following:
∞
 1 δ
2
ln  lim  ( [ x ] – [ x ] )! + ---  + ( sin q ) + ( cos q ) =
1 –1 –1 1 cosh p 1 – ( tanh p )
∑ -------------------------------------------------
2 2
- (EQ 4-1)
δ → ∞  δ  n
  2
n=0
given that 100% bioavailability of a single I.V. bolus dose is equal to 1, and both
doses contain an equal mass of active drug.
For the struggling pharmacokinetics student, we would like to show the veracity of
this statement. Of course, it is obvious that; the reverse of the transpose is equal to
the transpose of the inverse in matrix theory. i.e.:
1 –1 –1 1
[x ] = [x ] (EQ 4-2)
Also, it should be obvious that:
0! = 1 (EQ 4-3)
Consequently,
1 –1 –1 1
([x ] – [ x ] )! = 1 (EQ 4-4)
which means that:

∞
 1 δ cosh p 1 – ( tanh p ) -
2
ln  lim  1 + ---  + ( sin q ) + ( cos q ) = ∑ -------------------------------------------------
2 2
 
(EQ 4-5)
δ → ∞ δ  2
n
n=0
By definition,
1 δ
e =  1 + ---
 δ
(EQ 4-6)
and
2
1 = cosh p 1 – ( tanh p ) (EQ 4-7)
Thus:

Introduction
∞
1
∑ ----
2 2
ln e + ( sin q ) + ( cos q ) = - (EQ 4-8)
n
n=0
2
Also,
∞
1
2 = ∑ ----
2
-
n
(EQ 4-9)
n=0
and
1 = ln e (EQ 4-10)
and
2 2
1 = ( sin q ) + ( cos q ) (EQ 4-11)
So, as we observed in equation 1,
1+1 = 2 (EQ 4-12)
under the stated conditions, two I.V. bolus doses given simultaneously will have
twice as much available drug as a single I.V. bolus dose.
You will agree, however, equation 1-1 is obvious and therefore is more easily
understood by a pharmacokineticist!

CHAPTER 2 Mathematics Review
Author: Michael Makoid, Phillip Vuchetich and John Cobby

BASIC MATHEMATICAL SKILLS OBJECTIVES

1. Given a data set containing a pair of variables, the student will properly construct
(III) various graphs of the data.
2. Given various graphical representations of data, the student will calculate (III) the
slope and intercept by hand as well as using linear regression.
3. The student shall be able to interpret (V) the meaning of the slope and intercept
for the various types of data sets.
4. The student shall demonstrate (III) the proper procedures of mathematical and
algebraic manipulations.
5. The student shall demonstrate (III) the proper calculus procedures of integration
and differentiation.
6. The student shall demonstrate (III) the proper use of computers in graphical simu-
lations and problem solving.
7. Given information regarding the drug and the pharmacokinetic assumptions for
the model, the student will construct (III) models and develop (V) equations of the
ADME processes using LaPlace Transforms.
8. The student will interpret (IV) a given model mathematically.
9. The student will predict (IV) changes in the final result based on changes in vari-
ables throughout the model.
10. The student will correlate (V) the graphs of the data with the equations and mod-
els so generated.

Mathematics Review
2.1 Concepts of Mathematics

Pharmacokinetcs is a challenging field involving the application of mathematical
concepts to real situations involving the absorbtion, distribution, metabolism and
excretion of drugs in the body. In order to be successful with pharmacokinetics, a
certain amount of mathematical knowledge is essential.
This is just a review. This chapter is meant to review the concepts in mathematics essential for under-
Look it over. You should standing kinetics. These concepts are generally taught in other mathematical
be able to do all of these courses from algebra through calculus. For this reason, this chapter is presented as
manipulations.
a review rather than new material. For a more thorough discussion of any particu-
lar concept, refer to a college algebra or calculus text.
Included in this section are discussions of algebraic concepts, integration/differen-

tiation, graphical analysis, linear regression, non-linear regression and the LaPlace
transform. Pk Solutions is the computer program used in this course.
Something new - A critical concept introduced in this chapter is the LaPlace transform. The LaPlace
LaPlace transforms. transform is used to quickly solve (integrate) ordinary, linear differential equa-
Useful tool.
tions. The Scientist by Micromath Scientific Software, Inc.1 is available for work-
ing with the LaPlace transform for problems throughout the book.
1. MicroMath Scientific Software, Inc., P.O. Box 21550, Salt Lake City, UT 84121-0550,

Mathematics Review
2.2 Mathematical Preparation
2.2.1 ZERO AND INFINITY
Any number multiplied by zero equals zero. Any number multiplied by infinity
( ∞ ) equals infinity. Any number divided by zero is mathematically undefined.
Any number divided by infinity is mathematically undefined.
2.2.2 EXPRESSING LARGE AND SMALL NUMBERS
Large or small numbers can be expressed in a more compact way using indices.
5
How Does Scientific Examples: 316000 becomes 3.16 × 10
Notation Work?
–3
0.00708 becomes 7.08 ×10
In general a number takes the form:
n
A × 10
Where A is a value between 1 and 10, and n is a positive or negative integer
The value of the integer n is the number of places that the decimal point must be
moved to place it immediately to the right of the first non-zero digit. If the decimal
point has to be moved to its left then n is a positive integer; if to its right, n is a
negative integer.
Because this notation (sometimes referred to as “Scientific Notation”) uses indi-

ces, mathematical operations performed on numbers expressed in this way are sub-
ject to all the rules of indices; for these rules see Section 2.2.4.
A shorthand notation (AEn) may be used, especially in scientific papers. This may
n
be interpreted as A × 10 , as in the following example:
4
2.28E4 = 2.28 ×10 = 22800

Mathematics Review
2.2.3 SIGNIFICANT FIGURES
A significant figure is any digit used to represent a magnitude or quantity in the

place in which it stands. The digit may be zero (0) or any digit between 1 and 9.
For example:
TABLE 2-1 Significant Figures
Number of
Significant Significant
Value Figures Figures
(a) 572 2,5,7 3
(b) 37.10 0,1,3,7 4
(c) 10.65 x 104 0,1,6,5 4
(d) 0.693 3,6,9 3
(e) 0.0025 2,5 2
How do I determine the Examples (c) to (e) illustrate the exceptions to the above general rule. The value 10
number of significant raised to any power, as in example (c), does not contain any significant figures;
figures? hence in the example the four significant figures arise only from the 10.65. If one
or more zeros immediately follow a decimal point, as in example (e), these zeros
simply serve to locate the decimal point and are therefore not significant figures.
The use of a single zero preceding the decimal point, as in examples (d) and (e), is
a commendable practice which also serves to locate the decimal point; this zero is
therefore not a significant figure.
What do significant fig- Significant figures are used to indicate the precision of a value. For instance, a
ures mean? value recorded to three significant figures (e.g., 0.0602) implies that one can reli-
ably predict the value to 1 part in 999. This means that values of 0.0601, 0.0602,
and 0.0603 are measurably different. If these three values cannot be distinguished,
they should all be recorded to only two significant figures (0.060), a precision of 1
part in 99.
After performing calculations, always “round off” your result to the number of sig-
nificant figures that fairly represent its precision. Stating the result to more signifi-
cant figures than you can justify is misleading, at the very least!

Mathematics Review
2.2.4 RULES OF INDICES

n
What is an index? An index is the power to which a number is raised. Example: A where A is a
number, which may be positive or negative, and n is the index, which may be pos-
itive or negative. Sometimes n is referred to as the exponent, giving rise to the
general term, “Rules of Exponents”. There are three general rules which apply
when indices are used.
(a) Multiplication
A n n+m
=  --- × B
n m n+m n m
A ×A = A A ×B
B
(b) Division
n n n n–m
A-
------ = A
n–m A-
------ = A--- × B
m m  B
A B
(c) Raising to a Power
n m nm
(A ) = A
There are three noteworthy relationships involving indices:
(i) Negative Index
–n 1 –n
A = -----n- As n tends to infinity ( n → ∞ ) then A → 0 .
A
(ii) Fractional Index
1
---
n n
A = A
(iii) Zero Index
0
A = 1

Mathematics Review
2.2.5 LOGARITHMS
What is a logarithm? Some bodily processes, such as the glomerular filtration of drugs by the kidney,
are logarithmic in nature. Logarithms are simply a way of succinctly expressing a
number in scientific notation.
In general terms, if a number (A) is given by
n
A = 10 then log ( A ) = n
where ‘log’ signifies a logarithm to the base 10, and n is the value of the logarithm
of (A).
5
Example: 713000 becomes 7.13 × 10 ,
0.85 0.85 5 ( 5 + 0.85 ) 5.85

and 7.13 = 10 , thus 713000 becomes 10 × 10 = 10 = 10
and log ( 713000 ) = 5.85
Logarithms to the base 10 are known as Common Logarithms. The transformation

of a number (A) to its logarithm (n) is usually made from tables, or on a scientific
calculator; the reverse transformation of a logarithm to a number is made using
anti-logarithmic tables, or on a calculator.
What is the characteris- The number before the decimal point is called the characteristic and tells the place-
tic? the mantissa? ment of the decimal point (to the right if positive and to the left if negative). The
number after the decimal is the mantissa and is the logarithm of the string of num-
bers discounting the decimal place.
2.2.6 NATURAL LOGARITHMS

What is a natural loga- Instead of using 10 as a basis for logarithms, a natural base (e) is used. This natural
rithm? base is a fundamental property of any process, such as the glomerular filtration of a
drug, which proceeds at a rate controlled by the quantity of material yet to undergo
the process, such as drug in the blood. To eight significant figures, the value of the
transcendental function, e, is
∞
1 Where x is an inte-
e = 2.7182818 ... Strictly speaking, e = 1 + ∑ ---x!-
x=1
ger ranging from 1 to infinity ( ∞ ) ,

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∑ denotes the summation from x = 1 to x = ∞ , and

x=1
! is the factorial (e.g., 6! = 6x5x4x3x2x1= 720)
n
In general terms, if a number (A) is given by A = e , then by definition,
ln ( A ) = n
Where, ‘ln’ signifies the natural logarithm to the base e , and n is the value of the
natural logarithm of A .
Natural logarithms are sometimes known as Hyperbolic or Naperian Logarithms;

again tables are available and scientific calculators can do this automatically. The
anti-logarithm of a natural logarithm may be found from exponential tables, which
n
give the value of e for various values of n.
How are natural loga- Common and natural logarithms are related as follows:
rithms ln x and common
logarithms log x related? ln ( A ) = 2.303 × log ( A ) , and
log ( A ) = 0.4343 × ln ( A )
Because logarithms are, in reality, indices of either 10 or e , their use and manipu-
lation follow the rules of indices (See Section 2.2.4).
(a) Multiplication:
n m n m n+m
To multiply N × M , where N = e and M = e ; NM = e × e = e .
By definition, ln ( NM ) = n + m ; but
n = ln ( N ) and m = ln ( M ) , hence ln ( NM ) = ln ( N ) + ln ( M )
Thus, to multiply two numbers (N and M) we take the natural logarithms of each,
add them together, and then take the anti-logarithm (the exponent, in this case) of
the sum.

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(b) Division
ln  ----- = ln ( N ) – ln ( M )
N
 M
(c) Number Raised to a Power
m
ln ( N ) = m × ln ( N )
There are three noteworthy relationships involving logarithms:
(i) Number Raised to a Negative Power
) = – m × ln ( N ) = m × ln  ----
–m 1
ln ( N
N
–m
As m tends to infinity ( m → ∞ ) , then ln ( N ) → –∞
(ii) Number Raised to a Fractional Power
1
 ---
m
-
1
ln ( m N ) = ln  N  = ---- × ln ( N )
  m
(iii) Logarithm of Unity
ln ( 1 ) = log ( 1 ) = 0

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2.2.7 NEGATIVE LOGARITHMS
The number 0.00713 may be expressed as:
–3
7.13 ×10 , or
0.85 –3
10 × 10 , or
– 2.15
10 .
Hence, log ( 0.00713 ) = – 2.15 , which is the result generated by most calculators.
However, another representation of a negative logarithm (generally used by refer-

encing a log table):
log (0.00713) = 3.85
The 3 prior to the decimal point is known as the characteristic of the logarithm; it
can be negative (as in this case) or positive, but is never found in logarithmic
tables. The .85 following the decimal point is known as the mantissa of the loga-
rithm; it is always positive, and is found in logarithmic tables.
In fact 3 is a symbolic way of writing minus 3 (-3) for the characteristic. In every
case the algebraic sum of the characteristic and the mantissa gives the correct
value for the logarithm.
Example: log (0.00713) = 3.85
Add -3 and 0.85
Result is -2.15, which is the value of log ( 0.00713 )
The reason for this symbolism is that only positive mantissa can be read from anti-
logarithmic tables, and hence a positive mantissa must be the end result of any log-
arithmic manipulations. Note that while there are negative logarithms (when N <
1), they do not indicate that number itself is negative; the sign of a number (e.g., -
N) is determined only by inspection following the taking of anti-logarithms.

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2.2.8 USING LOGARITHMIC AND ANTI-LOGARITHMIC TABLES
Though the preferred method to using logarithms is with a calculator or computer,

the understanding of how the number is being manipulated may be important in
understanding the use of logarithms. (See the end of this chapter for Logarithm
tables).
(a) Find the log of (62.54):

1
1. convert 62.54 to scientific notation ---> 62.54 = 6.254 ×10 ;
2. Look up the mantissa for 6254 in a table of logarithms: it is 7962.
1 0.7962 1 1.7962
3. Hence, 6.254 ×10 = 10 × 10 = 10 and log ( 62.54 ) = 1.7962
(b) Find the log of (0.00329)

–3
1. 0.00329 = 3.29 ×10
2. The mantissa for 329 is 5172
3. Hence, log(0.00329) = 3.5172.
Note that in both examples the value of the characteristic is the integer power to
which 10 is raised when the number is written in scientific notation.
How do I multiply using (c) Multiply 62.54 by 0.00329
logarithms?
log (62.54) = 1.7972
log (0.00329) = 3.5172
log (62.54 + log (0.00329) = 1.7962+3.5172 = 1.7962-3+ 0.5172=-0.6866
0.6866=1.3134
(d) We wish to find anti-log (1.3134) Look up the anti-log for the 0.3134 (man-
tissa) in a table: it is 2058.
–1
Antilog (1.3134) = 2.058 ×10
Hence, antilog (1.3134) = 0.2058

How do I divide using log (62.54) - log (0.00329) = 1.796 - 3.5172=1.796 +3 - 0.5172=4.2788
logarithms?
antilog 4.2788 = 19002

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2.2.9 DIMENSIONS
What is a unit? There are three fundamental dimensions which are used in various combinations to
express the properties of matter. Each of these dimensions has been assigned a def-
inite basic unit, which acts as a reference standard.
TABLE 2-2 Dimensions
Dimensional
Dimension Symbol Unit Unit Symbol
Length L meter m
Mass M gram g
Time T second sec
How are units made big- In the metric system, which emerged from the French Revolution around 1799,
ger and smaller? there are various prefixes which precede the basic units and any derived units. The
prefixes indicate the factor by which the unit is multiplied. When the index of the
factor is positive the prefixes are Greek and have hard, consonant sounds. In con-
trast, when the index is negative, the prefixes are Latin and have soft, liquid
sounds. (see Table 2-3).
How big is big? Examples: An average adult male patient is assumed to have a mass of 70 kilo-
grams (70 kg). An average adult male patient is assumed to have a height of 180
centimeters (180 cm). A newly minted nickel has a mass of 5.000 g. Doses of
drugs are in the mg (10-3 g) range (occasionally g) never Kg (103 g) or larger. Stu-
dents have told me that the dose that they have calculated for their patient is 108 g
(converting to common system - ~ 100 tons). I doubt it. Get familiar with this sys-
tem. Note that the plural of Kg or cm is Kg or cm; do not add an “s”. In pharmacy
there are two derived units which are commonly used, even though they are
related to basic units. The Liter (L) is the volume measurement and is a cube 10
cm on a side (1L = (10cm)3 = 1000 cm3 ) while the concentration measurement
and has the units of Mass per Volume.
Why should I use units? Whenever the magnitude of a measured property is stated, it is imperative to state
the units of the measurement. Numbers are useless by themselves.
Example: The procainamide concentration range is 4-8 µ g/ml; stating the range
without units may lead to a potentially lethal error in which procainamide is
administered in a sufficient dose to attain a range of 4-8 mg/ml, which is 1000
times too large and would give rise to cardiac arrest.

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TABLE 2-3 Scale of Metric system and SI
Name Symbol Multiplication Factor Name Symbol Multiplication Factor

exa- E 18 deci- d –1
10 10
peta- P 15 centi- c –2
10 10
tera- T 12 milli- m –3
10 10
giga- G
10
9 micro- µ 10
–6
mega- M 6 nano- n –9
10 10
kilo- k 3 pico- p –12
10 10
hecto- h 2 femto- f –15
10 10
deca- da 1 atto- a –18
10 10
TABLE 2-4
Dimensional Unit
Dimension Symbol Unit Symbol
Volume V liter l
Concentration C grams/liter g/l

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2.2.10 DIMENSIONAL ANALYSIS

How are units useful? It is a general rule that the net dimensions (and units) on the two sides of any equa-
tion should be equal. If this is not so, the equation is necessarily meaningless.
Consider the following equation which defines the average concentration of a drug
FD
in blood after many repeated doses, ( C b )∞ = -----------
VKτ
Where:
• F is the fraction of the administered dose ultimately absorbed (Dimensions: none),
• D is the mass of the repeated dose (Dimension: M),
• V is the apparent volume of distribution of the drug (Dimension: V = L )
–1
• K is the apparent first-order rate constant for drug elimination (Dimension: T ),
• and τ is the dosing interval (Dimension: T )
Writing the dimensions relating to the properties of the right-hand side of the equa-
tion gives:
M - M
----------------------- = -----
–1 V
V⋅T ⋅T
M
Thus ( C b )∞ has the dimensions of ----- , which are correctly those of concentration.
V
Sometimes dimensional analysis can assist an investigator in proposing equations

which relate several properties one with the other. If the units cancel, and you end
up with the correct unit of measure, you probably did it right. If you obtain units
that do not make sense, it’s guaranteed sure that you did it wrong.

Mathematics Review
2.3 Calculus
What is Calculus? Calculus concerns either the rate of change of one property with another (differen-
tial calculus), such as the rate of change of drug concentrations in the blood with
time since administration, or the summation of infinitesimally small changes (inte-
gral calculus), such as the summation of changing drug concentrations to yield an
assessment of bioavailability. In this discussion a few general concepts will be pro-
vided, and it is suggested an understanding of graphical methods should precede
this discussion.
2.3.1 DIFFERENTIAL CALCULUS
2.3.2 NON-LINEAR GRAPHS
3
Consider the following relationship: y = x
TABLE 2-5 x, y sample data

x 0 1 2 3 4
y 0 1 8 27 64
As can be seen from the graph (Figure 2-1), a non-linear plot is produced, as
expected.
FIGURE 2-1. y=x3
70
60
50
40
30
20
10
0
1 2 3 4
(Question: How could the above data be modified to give a linear graph?)

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2.3.3 SLOPE OF NON-LINEAR GRAPH
As with a linear graph,
y2 – y1 ∆y
---------------- = ------
x2 – x1 ∆x
Where ∆y is the incremental change in y and ∆x is the incremental change in x
But, as can be seen (Figure 1), the slope is not constant over the range of the graph;
it increases as x increases. The slope is a measure of the change in y for a given
change in x. It may then be stated that:
“the rate of change of y with respect to x varies with the value of x.”
2.3.4 VALUE OF THE SLOPE
3
We need to find the value of the slope of the line y = x when x = 2 (See Figure
1). Hence, we may choose incremental changes in x which are located around
x ≈ 2.
FIGURE 2-2. ∆y / ∆x when x ≈ 2
∆y
------
x1 x2 ∆x y1 y2 ∆y ∆x
0 4 4 0 64 64 16.000
1 3 2 1 27 26 13.000
1.5 2.5 1.0 3.375 15.625 12.250 12.250
1.8 2.2 0.4 5.832 10.648 4.816 12.040
1.9 2.1 0.2 6.859 9.261 2.042 12.010
1.95 2.05 0.1 7.415 8.615 1.200 12.003
As may be seen, the value of the slope ∆-----y- tends towards a value of 12.000 as the
 ∆x 
magnitude of the incremental change in x becomes smaller around the chosen
value of 2.0. Were the chosen incremental changes in x infinitesimally small, the
true value of the slope (i.e., 12.000) would have appeared in the final column of
the above table.

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Calculus deals with infinitesimally small changes. When the value of ∆x is infini-
tesimally small it is written dx and is known as the derivative of x. Hence,
dy
------ = f ( x )
dx
Where dy/dx is the derivative of y with respect to x and f ( x ) indicates some func-
tion of x.
2.3.5 DIFFERENTIATION FROM FIRST PRINCIPLES
Differentiation is the process whereby the derivative of y with respect to x is

found. Thus the value of dy/dx, in this case, is calculated.
(a) Considering again the original expression:
3
y = x
(b) Let the value of y increase to y + dy because x increases to x + dx .
Hence,
3
y + dy = ( x + dx ) (EQ 2-13)
Multiplying out:
3 2 2 3
y + dy = x + 3x ( dx ) + 3x ( dx ) + ( dx ) (EQ 2-14)
(c) The change in y is obtained by subtraction of the original expression from the
last expression. (i.e., Eq. 2 - Eq. 1)
2 2 3
dy = 3x ( dx ) + 3x ( dx ) + ( dx ) (EQ 2-15)
Dividing throughout to obtain the derivative,
dy
------ = 3x 2 + 3x ( dx ) + ( dx )2
dx
When dx is infinitesimally small, its magnitude tends to zero ( dx → 0 ) . The limit-

ing value of this tendency must be dx = 0 . At this limit,

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dy
------ = 3x 2 (EQ 2-16)
dx
2
Hence the derivative of y with respect to x at any value of x is given by 3x .
(d) In section 2.3.4 we saw how the true value of the slope (i.e., dy/dx) would be
12.0 when x = 2 . This is confirmed by substituting in Equation 1-16.
dy
------ = 3x 2 = 3 ( 2 2 ) = 12
dx
2.3.6 RULE OF DIFFERENTIATION
Although the rate of change of one value with respect to another may be calculated
as above, there is a general rule for obtaining a derivative.
Let x be the independent variable value, y be the dependent variable value, A be a

constant, and n be an exponential power.
The general rule is:
n
If y = Ax
then
dy
------ = nAx n – 1
dx
The Rules of Indices may need to be used to obtain expressions in the form
n
y = Ax
(e.g., if y = 5 x)
2.3.7 THREE OTHER DERIVATIVES
0
(a) If y = Ax ,
then y = A (i.e., y is constant)

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dy
Hence, ------ = 0
dx
Thus the derivative of a constant is always zero.
(b) Accept that if y = ln ( x )
dy 1
then ------ = --- .
dx x
This derivative is important when considering apparent first-order processes, of

which many bodily processes (e.g., excretion of drugs) are examples.
Ax
(c) Accept that if y = Be where B and A are constants, and e is the natural
dy Ax
base then ------ = ABe
dx
This derivative will be useful in pharmacokinetics for finding the maximum and
minimum concentrations of drug in the blood following oral dosing.
2.3.8 A SEEMING ANOMALY
Consider the following two expressions:
n
(a) If y = Ax , then
dy n–1
------ = nAx
dx
n
(b) If y = Ax + A ,
dy n–1 n–1
then ------ = nAx + 0 = nAx
dx
Both of the original expressions, although different, have the same derivative. This
fact is recognized later when dealing with integral calculus.

Mathematics Review
2.3.9 INTEGRAL CALCULUS
Generally integral calculus is the reverse of differential calculus. As such it is used

to sum all the infinitesimally small units (dy) into the whole value (y).
Thus,
∫ dy = y , where ∫ is the symbol for integration.
2.3.10 RULE OF INTEGRATION
The derivative expression may be written:
dy
------ = Ax n , or
dx
n
dy = Ax ⋅ dx
To integrate,
∫ dy ∫ Ax dx = A ∫ x dx
n n
y = =
A general rule states:
n+1
Ax
A ∫ x dx = ---------------- + A
n
n+1
Where A is the constant of integration However, there is one exception - the rule
is not applicable if n = – 1
dy 2
Example: If ------ = 3x (See section 2.3.5),
dx
2+1
3x
then y = --------------- + A , and
2+1
3
y = x +A

Mathematics Review
2.3.11 THE CONSTANT OF INTEGRATION
There has to be a constant in the final integrated expression because of the seeming
3 3
anomaly referred to in section 2.3.8. As mentioned, both y = x and y = x + A
dy 2
will give, on differentiation, ------ = 3x .
dx
So whether or not a constant is present and, if so, what is its value, can only be
decided by other knowledge of the expression. Normally this other knowledge
takes the form of knowing the value of y when x = 0 .
In the case of our graphical example we know that when x = 0 , then y = 0 . The
integrated expression for this particular case is:
3
y = x + A , therefore
3
0 = 0 + A , thus A = 0
In some examples, such as first-order reaction rate kinetics, the value of A is not
zero.
2.3.12 THE EXCEPTION TO THE RULE
It occurs when n = – 1
1
y = A ∫ x dx = A ∫ --- dx
–1
x
Upon integration, y = A ⋅ ln ( x ) + A
This is the reverse of the derivative stated in section 2.3.10 (b).
2.3.13 A USEFUL INTEGRAL
Accept that if,
dy
------ = Be Ax
dx

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then,
Ax
Be
y = ----------- + A
A
This integral will be useful for equations which define the bioavailability of a drug
product.
2.3.14 EXAMPLE CALCULATIONS
(a) Consider,
2
c = 3t ( t – 2 ) + 5
Where c is the drug concentration in a dissolution fluid at time t .
Then, multiplying out,
3 2
c = 3t – 6t + 5
The rate of dissolution at time t is
dc
------ = 9t 2 – 12t
dt
So at any time, the rate may be calculated.
dc 2
(b) Consider, ------ = 3t ( t – 4 ) = 9t – 12t
dt
Then rearranging,
2
dc = 9t ⋅ dt – 12 ⋅ dt
The integral of c is:
∫ dc
3 2
c = = 3t + A – 6t + B

Mathematics Review
where B is a second constant.
Adding the two constants together,
3 2
c = 3t = 6t + D
where D = A + B
We know, from previous work, that when t = 0 , then c = 5
Substituting 5 = D , the final expression becomes:
2 2
c = 3t + 6t + 5
Which is the initial expression in example (a) above.
(c) Following administration of a drug as an intravenous injection,
– dC p
------------- = KC p
dt
Where C p is the plasma concentration of a drug at time t
K is the apparent first-order rate constant of elimination.
Rearranging,
1
– K ⋅ dt = ------ ⋅ dC p
Cp
1
– Kt = – K ∫ dt = ∫ -----
- ⋅ dC p
Cp
This integral is the exception to the rule (see section 2.3.12).
– Kt = ln ( C p ) + A
We know that when t = 0 , C p = ( C p ) 0 .

Mathematics Review
Substituting, 0 = ln ( C p )0 + A
Or,
A = – ln ( C p )0
Hence
– Kt = ln ( C p ) – ln ( C p ) 0
or,
ln ( C p ) = ln ( C p ) 0 – Kt
or,
– Kt
Cp = ( C p )0 ⋅ e

Mathematics Review
2.4 Graphs
Why do we graph? We would like to organize the chaotic world around us so that we can predict (see
into the future) and retrodict (see into the past) what will happen or has happened.
Our recorded observations are collectively known as data. We make a theory
about what we think is happening and that theory is expressed in an equation. That
determines our paradigm of how we see the world. This paradigm is expressed as
a graph. The language of science is mathematics and graphs are its pictures.
TABLE 2-6
English Science
Observations Data
Theory Equations
Paradigms (pictures) Graphs
What is a graph? A graph is simply a visual representation showing how one variable changes with
alteration of another variable. The simplest way to represent this relationship
between variables is to draw a picture. This pictorializing also is the simplest way
for the human mind to correlate, remember, interpolate and extrapolate perfect
data. An additional advantage is it enables the experimenter to average out small
deviations in experimental results (non-perfect, real data) from perfect data. For
example:
TABLE 2-7 Perfect vs. Real data
Perfect Real
-3 -5 -4.6
-2 -3 -3.4
-1 -1 -0.6
0 +1 +0.8
+1 +3 +3.4
+2 +5 +4.4

Mathematics Review
FIGURE 2-3. Plot of Perfect vs. Real data
-2
-4
-6
-3 -2 -1 0 1 2
Simply looking at the columns x and y (real) it might be difficult to see the rela-
tionship between the two variables. But looking at the graph, the relationship
becomes apparent. Thus, the graph is a great aid to clear thinking. For every graph
relating variables, there is an equation and, conversely for every equation there is a
graph. The plotting of graphs is comparatively simple. The reverse process of find-
ing an equation to fit a graph drawn from experimental data is more difficult,
except in the case of straight lines.
2.4.1 GRAPHICAL CONVENTIONS

How are graphs made? Certain conventions have been adopted to make the process of rendering a data set
to a graphical representation extremely simple.
The ‘y’ variable, known as the dependent variable, is depicted on the vertical axis
(ordinate); and the ‘x’ variable, known as the independent variable, is depicted on
the horizontal axis (abscissa). It is said that ‘y’ varies with respect to ‘x’ and not
‘x’ varies with ‘y’.
A decision as to which of the two related variables is dependent can only be made
be considering the nature of the experiment. To illustrate, the plasma concentration
of a drug given by IV bolus depends on time. Time does not depend on the plasma
concentration. Consequently, plasma concentration would be depicted on the ‘y’
axis and time on the ‘x’ axis.

Mathematics Review
Any point in the defined space of the graph has a unique set of coordinates: 1) the
‘x’ value which is the distance along the ‘x’ axis out from the ‘y’ axis and always
comes first; and 2) the ‘y’ value which is the distance, along the ‘y’ axis up or
down from the ‘x’ axis, and always comes second. Several points are shown in
Figure 2. For example, (0,1) is on the line and (1,0) is not.
The intersection of x and y axis is the origin with the coordinates of (0,0). In two
dimensional spaces, the graph is divided into 4 quadrants from (0,0), numbered
with Roman numerals from I through IV. It should be readily apparent that the
coordinates for all points within a particular quadrant are of the same sign type i.e.,
TABLE 2-8 Quadrants on a cartesian graph

Quadrant II (-x, +y) Quadrant I (+x, +y)
Quadrant III (-x, -y) Quadrant IV (+x, -y)
A line (or curve) on a graph is made up of an infinite number of points, each of

which has coordinates that satisfy a given equation. For example, each point on the
line in Figure 2 is such at its coordinates fit the equation y = 2x + 1 . That is for
any value of x (the independent variable), multiplying the x value by 2 and adding
1 results in the y value (the dependent variable).
2.4.2 STRAIGHT LINE GRAPHS

What is a straight line? A graph is a straight line (linear) only if the equation from which it is derived has
the form
y = mx + b
Where:
• y = dependent variable
• x = independent variable
• m = slope of the straight line = ∆
-----y-
∆x
• b = the y intercept (when x = 0)
• or if the equation can be “linearized”, e.g.,
mx′
y′ = b′e is not linear. However. ln y′ = ln b′ + mx′
is of the same general form as: y = b + mx

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and consequently a plot of ln y′ (the dependent variable) versus x′ (the indepen-

dent variable) will yield a straight line with a slope of m and an intercept of ln b′ .
Expressions of any other form are non linear. For example:
An expression relating the plasma concentration of a drug ( C p ) over time ( t ) .
– Kt
C p = C p0 e
this relationship put in linear perspective yields:
ln C p = ln C p0 – Kt , which is in the form
y = b + mx
The graphs that yield a straight line are the ones with the ordinate being ln C p0 ,
and the abscissa being t .
Any other combination of functions of C p and t will be non-linear, e.g.,
• C p versus t
• C p versus ln t
• ln C p versus ln t
The appropriate use of a natural logarithm in this case serves to produce linearity.
However, the use of logarithms does not automatically straighten a curved line in
all examples. Some relationships between two variables can never be resolved into
( n – m) (n – m + 1) x
a single straight line, e.g., y = k 0 + k 1 x + k2 x + … + ( k n )x
where n ≥ 2 ;n = m + 1 or
K a FD Kt –K t
C p = ------------------------- ⋅ ( e – e a )
V ( Ka – K )
(It is possible to resolve this equation into the summation of two linear graphs
which will be shown subsequently.)

Mathematics Review
2.4.3 THE SLOPE OF A LINEAR GRAPH (M)

What is the slope of a From the equation a prediction may be made as to whether the slope is positive or
straight line? negative. In the previous example, the slope is negative, i.e: m = – K
TABLE 2-9 Sample data of caffeine elimination
µg
C p  --------
t (min)  mL ln C p
12 3.75 1.322
40 2.80 1.030
65 2.12 0.751
90 1.55 0.438
125 1.23 0.207
173 0.72 -0.329
The differences in both the y-values and the x-values may be measured graphically
to obtain the value of the slope, m. Then knowing the value of m, the value of K
may be found.
FIGURE 2-4. Plasma Concentration ( C p ) of caffeine over time
101
g/mL)
u
Caffeine Concentration (
100
10-1
0 50 100 150 200
Time (min)

Mathematics Review
2.4.4 LINEAR REGRESSION: OBTAINING THE SLOPE OF THE LINE

The equation for a straight line is:
y = m⋅x+b
• y is the dependent variable
• x is the independent variable
• m is the slope of the line
• b is the intercept of the line
The equation for the slope of the line using linear regression is:
( Σ ( x ) ⋅ Σ ( y ) ) – ( n ⋅ Σ ( x ⋅ y ) -)
m = --------------------------------------------------------------------
2 2
[ Σ ( x ) ] – ( n ⋅ Σ( x ) )
And the intercept is b = y – ( m ⋅ x )
TABLE 2-10 Linear Regression for data in table 2-9
2
X Y X X⋅Y
12 1.322 144 15.864
40 1.030 1600 41.2
65 0.751 4225 48.815
90 0.438 8100 39.42
125 0.207 15625 25.875
173 -0.329 29929 -56.917
ΣX = 505 ΣY = 3.239 2
ΣX = 59623 ΣXY = 114.257
2
( ΣX ) = 255025
Σx Σy
x = ------ = 4.167 y = ------ = 0.5398
n n
Using the data from table 2-10 in the equation for the slope of the line
( 505 ⋅ 3.239 ) – ( 6 ⋅ 114.257 ) ·
m = --------------------------------------------------------------------- = – 0.01014
255025 – ( 6 ⋅ 59623 )
and the intercept would be b = 0.5398 – ( – 0.01014 ⋅ 4.167 ) = 1.4229 .

Note that this is
ln C . In oder to find the C p0 , the anti-ln of b must be taken. i.e.
b 1.4229
Cpo = e = e = 4.15

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It is important to realize that you may not simply take any two data pairs in the
data set to get the slope. In the above data, if we simply took two successive data
pairs from the six data pairs in the set, this would result in five different slopes
( ∆x ⁄ ∆y ) ranging from -0.0066 to -0.0125 as shown in table 2-11. Clearly, this is
unacceptable. Even to guess, you must plot the data, eyeball the best fit line by
placing your clear straight edge through the points so that it is as close to the data
as possible and look to make sure that there are an equal number of points above
the line as below. Then take the data pairs from the line, not the data set.
TABLE 2-11 Sample slope data from figure 2-4
∆y
------
Time (x) ln Conc. (y) ∆x ∆y ∆x
12 1.322 -28 0.292 -0.0104
40 1.030 -25 0.28 -0.0112
65 0.751 -25 0.312 -0.0125
90 0.438 -35 0.231 -0.0066
125 0.207 -48 0.536 -0.0112
173 -0.329
2.4.5 PARALLEL LINES

Two straight lines are parallel if they have the same slope.
Calculating for the intercept of a linear graph (b):
(a) Not knowing the value of m; The graph may be extrapolated, or calcu-
lations performed, at the situation where t = 0 . In this case b = ln C p0 .
(b) Knowing the value of m;

• There are two ways: for any point on the graph: y 1 = mx 1 + b and b = y 1 – mx 1
Hence, b may be calculated from a knowledge of y 1 and x 1 .
• Secondly, the graph may be extrapolated or calculations performed, at the situation where
t = 0 . In this case, b = ln C p

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2.4.6 GRAPHICAL EXTRAPOLATIONS

How far can I predict? It is dangerous to extrapolate on non-linear graphs, and it is unwise to extrapolate
too far on linear graphs. Most often extrapolation is used to find the value of y at a
selected value of x.
If the size of the graph does not permit physical extrapolation to the desired value,
the required result may be obtained by calculation. The values of m and b must be
found as shown above. Then: y' = mx' + b , where x' is the selected value of x,
and y' is the new calculated value for y.
2.4.7 SIGNIFICANCE OF THE STRAIGHT LINE
The more closely the experimental points fit the best line, and the higher the num-
ber of points, the more significant is the relationship between y and x. As you may
expect, statistical parameters may be calculated to indicate the significance.
What good is a straight By using all the experimental data points, calculations may be made to find the
line? optimum values of the slope m, and the intercept, b. From these values the corre-
lation coefficient (r).and the t-value may be obtained to indicate the significance.
Exact details of the theory are available in any statistical book, and the calculations
may most easily be performed by a computer using The Scientist or PKAnalyst in
this course.
The advantage of computer calculation is that it gives the one and only best fit to
the points, and eliminates subjective fitting of a line to the data.
2.4.8 GRAPHICAL HONESTY

How many points are Any graph drawn from 2 points is scientifically invalid. Preferably, straight-line
needed? graphs should have at least 3 - 5 points, and non-linear graphs a few points more.
Can I discard points that As a graph is a visual representation which enables the experimenter to average
don’t fit? out the small deviations in results from the “perfect” result, no one result can be
unjustifiably ignored when the best fitting line is drawn. Still, an “errant” point
may be justifiably ignored if there were unusual experimental circumstances
which may have caused the deviation. Thus it is not justifiable to omit a point
solely because it “does not fit”.
2.4.9 AXES WITH UNEQUAL SCALES
In mathematical studies, the scales of the x and y are almost always equal but very
often in plotting chemical relations the two factors are so very different in magni-

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tude that this can not be done. Consequently, it must be borne in mind that the rela-
tionship between the variables is given by the scales assigned to the abscissa and
ordinate rather than the number of squares counted out from the origin.
FIGURE 2-5. y = 0.1 x
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
0 2 4 6 8 10
10
8
6
4
2
0
0 2 4 6 8 10
For example (shown in Figure 2-5), these two parabolic curves represent the same
equation the only difference is the scales are different along the y axis.
Frequently it is not convenient to have the origin of the graph coincide with the
lower left hand corner of the coordinate paper. Full utilization of the paper with
suitable intervals is the one criteria for deciding how to plot a curve from the
experimental data. For example, the curve below (Figure 2-6) is poorly planned,
where the following (Figure 2-7) is a better way of representing the gas law
PV = nRT

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FIGURE 2-6. Poorly presented graph
50
40
30
20
10
0
0 4 8 12 16 20
FIGURE 2-7. Well arranged graph
25
20
15
10
5
0
1 2 3 4 5 6 7 8 9 10
P ( )
2.4.10 GRAPHS OF LOGARITHMIC FUNCTIONS
2
Previously variables were raised to constant powers; as y = x . In this section
x
constants are raised to variable powers; as y = 2 . Equations of this kind in which
the exponent is a variable are called (naturally) exponential equations. The most
x
important exponential equation is where e is plotted against x .

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2.4.11 SEMILOGARITHMIC COORDINATES
Exponential or logarithmic equations are very common in physical chemical phe-

nomenon. One of the best ways of determining whether or not a given set of phe-
nomenon can be expressed by a logarithmic or exponential equation is to plot the
logarithm of one property against another property. Frequently a straight line is
obtained and its equation can be readily found. For example:
In the following table the plasma concentration ( C p ) of the immunosuppressant

cyclosporine was measured after a single dose (4mg/kg) as a function of time.
TABLE 2-12 Plasma concentration of cyclosporine
ng
Concentration ------
Time (hours) ml
0.25 1900
.75 1500
1.5 1300
4 900
6 600
8 390
D’mello et al., Res. Comm. Chem. Path. Pharm. 1989: 64 (3):441-446
These can be illustrated in three different ways (Figures 2-8, 2-9, 2-10),
• Concentration vs. time directly
• Log concentration vs. time directly
• Log concentration vs. time with concentration plotted directly on to log scale of ordinate.
FIGURE 2-8. Concentration (ng/ml) vs. time (hr)
2000
1800
1600
1400
1200
1000
800
600
400
200
0 1 2 3 4 5 6 7 8

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FIGURE 2-9. Log Concentration vs. time
3.200
Log Concentration - Time Curve
3.100
3.000
2.900
2.800
2.700
2.600
2.500
2.400
2.300
0 1 2 3 4 5 6 7 8
FIGURE 2-10. Log concentration (on log scale) vs. time
10000
1000
100
0 1 2 3 4 5 6 7 8
Graphing is much easier because the graph paper itself takes the place of a loga-
rithmic table, as shown in Figure 1-10.
Only the mantissa is designated by the graph paper. Scaling of the ordinate for the
characteristic is necessary. The general equation y = Be ax can be expressed as a
straight line by basic laws of indices.
ax
ln y = ln B + ln ( e ) → ln y = ln B + ax or ln y = ax + ln B
One axis is printed with logarithmic spacing, and the other with arithmetic spac-
ing. It is used when a graph must be plotted as in the example (Figure 1-4)
y = log [ C p ] and x = t .

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In this example, the vertical logarithmic axis is labelled “Plasma concentration of

cyclosporine” and the values plotted are the ordinary values of [ C p ] . Thus, there is
no need to use logarithmic tables, because the logarithmic spacing is responsible
for obtaining a straight line.
Two problems may occur when graphing on a logarithmic mantissa:
a) there are not enough cycles to incorporate all the data
b) obtaining the value of the slope is difficult. In this instance the slope is given by:
y2 – y1 ln [ C p ] 2 – ln [ C p ] 1
m = ---------------
- = --------------------------------------------
x2 – x1 t2 – t1
Hence, before calculating the value of m, the two selected values of [ Cp ] 1 and [ Cp ] 2
must be converted, using a calculator, to ln [ Cp ] 1 and ln [ C p ] 2 in order to satisfy the
equation. The same problem may arise in obtaining the intercept value, b.
The two problems may be avoided by plotting the same data on ordinary paper, in
which case the vertical axis is labelled “log plasma concentration”. However, in
this instance the ordinary values of [ C p ] must be converted to ln [ Cp ] prior to plot-
ting. It is the ln [ Cp ] values which are then plotted.
The calculation of the slope is direct in this case, as the values of y 1 and y 2 may be
read from the graph. Hence, one must consider the relative merits of semilogarith-
mic and ordinary paper before deciding which to use when a log plot is called for.
In the case of semilog graphs the slope may be found in a slightly different manner,
i.e., taking any convenient point on the line ( y 1 ) we usually take the as the second
point, ( y 2) one half of ( y 1 ) . Thus,
y1 
ln  ------------------- ln  ----------
- 1
ln y 1 – ln ( ( 1 ⁄ 2 )y 1 )  ( 1 ⁄ 2 )y 1  1⁄2 ln 2 - 0.693
m = ----------------------------------------------
- = ------------------------------
- = --------------------- = ------------- = -------------
t 1 – t2 t 1 – t2 t 1 – t2 t1 – t2 –t1 ⁄ 2
(in which case, t 2 – t 1 is called the half-life t½ ). Since t1 < t2 , then t1 – t2 = –t1 ⁄ 2
0.693 0.693
because m = ------------- = – k
–t1 ⁄ 2
and k = ------------- .
t1 ⁄ 2

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2.4.12 LOG - LOG COORDINATES
a
Functions of the type y = Bx give straight lines when plotted with logarithms
along both axis.
i.e., equation in logarithmic form is:
log y = log B + a log x or log y = a log x + log b which is in the form
y = mx + b . This is directly applicable to parabolic and hyperbolic equations

previously discussed (see Figure 1-5).
2.4.13 PITFALLS OF GRAPHING: POOR TECHNIQUE
The utility of these procedures requires proper graphing techniques. The picture
that we draw can cause formation of conceptualizations and correlations of the
data that are inconsistent with the real world based simply on a bad picture. Conse-
quently the picture must be properly executed.
The most common error is improper axes labelling. On a single axis of rectilinear
coordinate paper (standard graph paper), a similar distance between two points
corresponds to a similar difference between 2 numbers. Thus,
FIGURE 2-11. Graphing using standard number spacing
40
30
20
10
0
0 5 10 15 20 25 30

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FIGURE 2-12. Nonstandard (incorrect) graph
40
30
20
10
1
0
0 2 5 10 20 30
Obviously, the distance (Time) on the graph 12 between 0 and 2 hours should not
be the same as the distance between 10 and 20 hours. It is, and therefore Figure 2-
12 is wrong.
Similarly, the use of similar paper may result in some confusion. With logarithms
the mantissa for any string of numbers, differing only by decimal point placement,
is the same. What differentiates one number from another, in this case, is the char-
acteristic. Thus,
TABLE 2-13 Logarithmic graphing
Number Mantissa Characteristic Log

234 .3692 2 2.3692
23.4 .3692 1 1.3692
2.34 .3692 0 0.3692
0.234 .3692 -1 1.3692
The paper automatically determines the relationship between strings of numbers

(mantissa) by the logarithmic differences between the numbers on the axis within a
cycle. The student must determine the order of magnitude (characteristic) to be rel-
egated to each cycle.

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FIGURE 2-13. Logarithmic mantissa
Logarithmic Plot
103
234
102
23.4
101
Y axis (units)
2.34
100
0.234
10-1
1.0 1.5 2.0 2.5 3.0 3.5 4.0
X axis (units)
Thus, we see, in Figure 2-13, the cycle on the semilog paper to relate to orders of
magnitude (e.g., 1, 10, 100, 1000, etc.) and consequently the characteristic of the
exponent.
The third common problem is labelling the log axis as log “y”. This is improper. It
is obvious from the spacing on the paper that this function is logarithmic, and thus
the axis is simply labelled “y”.
There are almost as many different errors as there are students and it is impossible
to list them all. These few examples should alert you to possible problems.
2.4.14 GRAPHICAL ANALYSIS
We will look at several different types of plots of data:
FIGURE 2-14. Straight line going down on semi-log paper
0 1 2 3 4 5

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Find the slope by taking any two values on the Y axis such that the smaller value is
one half of the larger. The time that it takes to go from the larger to the smaller is
the half-life. Dividing 0.693 by the half-life yields the rate constant.
Extrapolating the line back to t = 0 yields the intercept.
FIGURE 2-15. Curved line which plateaus on semi-log paper.
0 2 4 6 8 10 12
FIGURE 2-16. Curved line which goes up and then straight down on semi-log paper.
0 5 10 15 20 25
Find the terminal slope by taking any two values on the Y axis such that the
smaller value is one half of the larger. The time that it takes to go from the larger to
the smaller is the half-life. Dividing 0.693 by the half-life yields the rate constant.
Plot type one is reasonably easily evaluated. There are 2 important things that can
be obtained: Slope and Intercept. However, the slope and intercept have different
meanings dependent on the data set type plotted. The slope is the summation of all
the ways that the drug is eliminated, -K.

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TABLE 2-14 Plot type 1 examples
Data Type Y axis X axis Slope Intercept

IV Bolus Parent Drug Conc. parent compound Time -K dose
C p0 = -----------
Vd
IV Bolus Parent dXu Time -K Kr ⋅ X 0
---------- urine rate of excretion
dt (mid)
parent compound
IV Bolus Parent Xu ∞ – Xu Cumulative urine Time -K kr
--------------
data K ⋅ X0
Plot type two is not usually evaluated in its present form as only the plateau value
can be obtained easily. But again it has different meanings dependent on the data
plotted.
TABLE 2-15 Plot Type 2 examples
Data Type Y axis X axis Plateau Value

IV Bolus Parent Xu Cumulative urine Time kr
Xu ∞ = --------------
data parent compound K ⋅ X0
IV Infusion Drug concentration Time Q Q

Parent parent compound ( C p )ss = ------------ = ----
K⋅V cl
Usually urine data of this type (parent compound - IV bolus) is replotted and eval-
uated as plot 1 (above). Infusion data can be replotted using the same techniques,
but usually is not.
Plot type 3 must be stripped of the second rate constant from the early time points,
thus:
There are 3 things that can be obtained from the plot: the terminal slope (the
smaller rate constant), the slope of the stripped line (the larger rate constant) and
the intercept. The rate constants obtained from a caternary chain (drug moving
from one box to another in sequence in compartmental modeling) are the summa-
tion of all the ways that the drug is eliminated from the previous compartment and
all the ways the drug is eliminated from the compartment under consideration. See
LaPlace Transforms for further discussion.
Again, dependent on the data set type being plotted they will have different values.

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TABLE 2-16 Plot Type 3 examples
Data
Type Y axis X axis S1 S2 Intercept
IV Bolus Metabolite conc. Time -K small -Klarge km ⋅ X 0
Parent -------------------------------------------------------
( K l arg e – K smal l ) ⋅ V dm
IV Bolus dXmu
--------------- excretion
Time -K small -Klarge k mu ⋅ k m ⋅ X 0
Parent dt (mid) -----------------------------------
-
K l arg e – K smal l
rate of metabolite
into urine
Oral Drug conc. Time -K small -Klarge k a ⋅ fX 0
---------------------------------------------------
-
( K l arg e – K smal l ) ⋅ V d

Mathematics Review
2.5 Pharmacokinetic MoKdeling

It has been observed that, after the administration of a drug, the concentration of
the drug in the body appear to be able to be described by exponential equations.
Thus, it appears that, even though the processes by which the drug is absorbed. dis-
tributed, metabolized and excreted (ADME) may be very complex, the kinetics
(math) which mimics these processes is made up of relatively simple first order
processes and is called first order pharmacokinetics. A second observation is that
the resulting concentration is proportional to dose. When this is true, the kinetics is
called linear. When this math is applied to the safe and effective therapeutic man-
agement of an individual patient, it is called clinical pharmacokinetics. Thus, in
clinical pharmacokinetics, we monitor plasma concentrations of drugs and suggest
dosage regimens which will keep the concentration of drug within the desired ther-
apeutic range. Pharmacodynamics refers to the relationship between the drug con-
centration at the receptor and the intensity of pharmacological (or toxicological)
response. It is important to realize that we want to control the pharmacological
response. We do that indirectly by controlling the plasma concentration. In order
for this to work, we assume kinetic homogeneity, which is that there is a predict-
able relationship between drug concentration in the plasma (which we can mea-
sure) and drug concentration at the receptor site (which we can not measure). This
assumption is the basis for all clinical therapeutics.
Models are simply mathematical constructs (pictures) which seem to explain the
relationship of concentration with time (equations) when drugs are given to a per-
son (or an animal). These models are useful to predict the time course of drugs in
the body and to allow us to maintain drug concentration in the therapeutic range
(optimize therapy). The simplest model is the one used to explain the observations.
We model to summarize data, to predict what would happen to the patient given a
dosage regimen, to conceptualize what might be happening in disease states and to
compare products. In every case, the observations come first and the explanation
next. Given that a data set fits a model, the model can be used to answer several
different types of questions about the drug and how the patient handles the drug
(its disposition), for example: if the drug were to be given by an oral dose, how
much is absorbed and how fast? Are there things which might affect the absorp-
tion, such as food or excipients in the dosage form itself. What would happen if the
drug were to be given on a multiple dose regimen? What if we increased the dose?
etc.

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You should be able to:

• be facile in the use of the equations. You should be able to graphically manipulate data sets and
extract pharmacokinetic parameters, applying the appropriate equations or variations of them.
• define all new words used in this section. e g.: Succinctly define, stating rigorously the meaning
of any symbols used and the dimensions of measurement.
• compare and contrast new concepts used in this section. e. g.: rate and rate constant, zero and
first order kinetics, bolus and infusion methods, excretion and elimination, the assumptions
made in pharmacokinetic models with physiological reality. Why can these assumptions be
made?
• pictorially represent any two variables (graph) one vs. the other. e.g. for each of the following
pairs of variables (ordinate against abscissa), draw a graph illustrating the qualitative profile of
their relationship. Where appropriate, indicate the nature of important slopes, intercepts, and
values. Unless you specifically indicate on your plot that semi-log paper is being considered
(write “S-L”), it will be assumed that rectilinear paper is being considered. Graphs are for a
drug given by IV Bolus where applicable.
2.5.1 MAKING A MODEL
The differential equations used result from the

ka model which is our conceptualization of what is
X happening to the drug in the body.
The box (compartment) is the area of interest. We

want to find out how the mass of drug, X , changes
with time in that compartment, the rate, and how the rates change with time, the
differential equations.
How do we make a dif- The picture that we build is made up of building blocks, consisting of the arrow
ferential equation? and what the arrow touches. The arrow demonstrates how quickly the mass of
drug, X , declines. The arrow times the box that the arrow touches = the rate. Rates
can go in, i.e. arrows pointing to a box mean drug is going in (+ rate). Rates can go
out, i.e. arrows pointing away means drug is going out (- rate). Rate = rate constant
(arrow) times mass of drug (box). So the arrow and box really is a pictorial repre-
sentation of a rate where the rate is the rate constant on the top of the arrow times
what the tail of the arrow touches.
Again, the rate constant, k , tells the magnitude of the rate, k⋅X.
Consider the following simple chain:

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k12 k23
X1 X2 X3
The building blocks are k 12 ⋅ X1 and k 23 ⋅ X2 . Every arrow that touches the compart-
ment of interest becomes part of the differential equation. If the arrow goes to the
box, it’s positive; if it goes away from the box, it’s negative.
To find dX1 ⁄ dt (the rate of change of X 1 with time), we simply add up all of the
rates which affect X1 (all of the arrows that touch X1 )
dX 1
--------- = – k 12 ⋅ X 1
dt
and thus:
dX 2
--------- = k 12 ⋅ X 1 – k 23 ⋅ X2
dt
dX 3
--------- = k 23 ⋅ X 2
dt
(Note: the first subscript of the rate constant and the subscript of the box from
which it originates are the same.)
You should be able to develop the series of interdependent differential equations

which would result from any model. The integration of those equations by use of
the Laplace Table is done by transforming each piece of the equation into the
Laplace domain (looking it up on the table and substituting). The algebra per-
formed solves for the time dependent variable: put everything except the variable
(including the operator, s) on the right side and put the variable on the left. Find the
resulting relationship on the left side of the table. The corresponding equation on
the right side of the table in the integrated form.
You should be able to integrate any differential equation developed from any
model (within reason) that we can conceptualize.
(Note: Each subsequent variable is dependent on the ones that precedes it. In fact,
the solutions to the preceding variables are substituted into the differential to
remove all but one of the time dependent functions - the one that we are currently
attempting to solve.)

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2.5.2 ONE COMPARTMENT OPEN MODEL
A simplified picture (mathematical construct) of the way the body handles drug is
one where the body can be conceived to be a rapidly stirred beaker of water (a sin-
gle compartment). We put the drug in and the rate at which the drug goes away is
proportional to how much is present (first order). Thus the assumptions are:
• Body homogeneous (one compartment)
• Distribution instantaneous
• Concentration proportional to dose (linear)
• Rate of elimination proportional to how much is there. (First order)
It is important to note that we know some of these assumptions are not true. It is of
little consequence, as the data acts as if these were true for many drugs. The visual
image which is useful is one of a single box and a single arrow going out of the
box depicting one compartment with linear kinetics. The dose is placed in the box
and is eliminated by first order processes. In many cases, more complicated mod-
els (more boxes) are necessary to mathematically mimic the observed plasma ver-
sus time profile when one or more of these assumptions are not accurate. For
example, the two compartment (or multi-compartment) model results when the
body is assumed to not be homogeneous and distribution is not instantaneous.

Mathematics Review
2.6 The LaPlace Transform

Why do we need to One of the important facets of biopharmaceutics is a familiarity with the principles
know the LaPlace trans- of pharmacokinetics. This latter discipline describes the study of the dynamic pro-
form? cesses by which the body “handles” or “disposes of” an administered drug. These
processes (absorption, distribution, metabolism, and excretion (ADME) are
dynamic in that they represent the time-dependent changes occurring to the drug.
Thus, in pharmacokinetics the time course of these changes, which overall
describe the fate of the administered drug, is described mathematically. If the
mathematical principles are understood, it is then possible to use pharmacokinetics
in clinical practice, such as the design of rational dosage regimens (T.S. Foster and
D.U.A. Bourne, Amer. J. Hosp. Pharm., 34, 70-75 (1977). Understanding
(Bloom’s level 4) is not simply memorizing (Bloom’s level 1) nor calculating
using a memorized equation (Bloom’s level 3). The authors believe that the proper
conceptualizing of the process and the subsequent derivation of the appropriate
equations will lead to an understanding of the mathematical principles, and thus, a
better, more optimal dosing regimen.
Since a mathematical description of the time-dependent ADME processes is

required, it becomes necessary to deal with their corresponding rate equations.
Inevitably this will involve calculus (mainly integral calculus). However, the
LaPlace Transform provides a method whereby calculus can be performed with
minimal trauma. If a conscientious effort to learn the method is made and applied,
a potentially serious obstacle (the fear of calculus) to the understanding and appre-
ciation of biopharmaceutics will be removed. Indeed, many students will find they
no longer fear integration and are thus free to comprehend the principles underly-
ing pharmacokinetics, which, after all, is the primary aim. So, the LaPlace Trans-
form is a tool which is of great assistance in pharmacokinetics; its utility and
importance should not be lightly disregarded.
The LaPlace Trans- There is, of course, a theoretical background to the LaPlace Transform. However,
form: What Is It? it can be used without recourse to a complete theoretical discussion, though appro-
priate pharmaceutical use of the method is found in the following references:
M. Mayersohn and M. Gibaldi, Amer. J. Pharm. Ed., 34, 608-614 (1970).
M. Gibaldi and D. Perrier, “Pharmacokinetics”, Marcel Dekker, pp. 267-272

(1975).
Basically, the LaPlace Transform is used to solve (integrate) ordinary, linear differ-
ential equations. In pharmacokinetics such equations are zero and first-order rate
equations in which the independent variable is time. For instance, if a differential
equation describing the rate of change of the mass of drug in the body with time is

Mathematics Review
integrated, the final equation will describe the mass of drug actually in the body at
any time.
The procedure used is to replace the Independent variable (time) by a function

containing the LaPlace Operator, whose symbol is “s”. In doing so we have
replaced the time domain by a complex domain. This is analogous to replacing a
number by its logarithm. Once in the complex domain, the transformed function
may be manipulated by regular algebraic methods. Then the final expression in the
complex domain is replaced by its equivalent in the time domain, yielding the inte-
grated equation. This ultimate process is analogous to taking an antilogarithm.
2.6.1 TABLE OF LAPLACE TRANSFORMS

A table of useful LaPlace The replacement of expressions in one domain by their equivalents in another is
transforms is given in accomplished by reference to tables. One column shows time domain expressions,
Section 2.7. Page 2-56.
stated as f ( t ) , and second column shows the corresponding complex domain
expressions, stated as the LaPlace Transform. Note that “ f ( t ) ” simply means
– at
“some function of time”. For example, when f ( t ) is Be , then the LaPlace
Transform is B ⁄ ( s + a ) , where “B” is a constant and “a” is a rate constant
For example, when the LaPlace Transform is A⁄s

2
, then f ( t ) is At .
2.6.2 SYMBOLISM
For simplicity in writing transformed rate expressions (and to distinguish them

from untransformed (time domain) expressions), the following symbolism will be
employed:
“a bar will be placed over the dependent variable which is being transformed”.
Example:
If X is the mass of unchanged drug in the body at any time, then X is the LaPlace
Transform of this mass.

Mathematics Review
2.6.3 CONVENTIONS USED IN DRAWING PHARMACOKINETIC SCHEMA.
When drugs enter the body, they will encounter many different fates. It is impor-
tant to set up the possible fates of the drug by creating a well thought out flow
chart or scheme in order to follow all the events that are occurring in the body as
described by the pharmacokinetic description of the drug. For example, a drug
may be excreted unchanged or may undergo hepatic metabolism to yield active or
inactive metabolites. All of these components are part of pharmacokinetics, which
by definition, includes ADME (the Absorption, Distribution, Metabolism and
Excretion of drugs), and must be considered. This flow chart becomes the back-
bone or the framework upon which to build the equations which describe the phar-
macokinetics of the drug. The differential equations result as a direct consequence
of the flow chart. Using Laplace transforms, the integration of these differential
equations are simplified and provide the pharmacokineticist to (easily?) keep track
of all of the variables in the equation. If the drug scheme or flow chart is set up
incorrectly, this would have a definite negative impact or the expected equations
(as well as the answers and your grade). Below are two examples of how to con-
struct a flow chart. Note that not all drugs follow the same flow chart and it is
quite possible that you will need only to use a portion of these examples when con-
struction your own.
In general, schema are relatively consistent in the placement of the compartments

in relationship to one another. You might consider, for example a drug, given by
IV bolus, which is metabolized and both the metabolite and the parent compound
are excreted unchanged as shown below:
Feces Body Urine
Dose
Parent Compound kf ku
Xf X Xu
km
kmf kmu
Metabolite Xmf Xm Xmu

Mathematics Review
Using the pharmacokinetic symbolism from chapter one, the compartments are
named and placed: metabolites below (or above the plane of the parent com-
pound): compounds going into the urine, to the right; and compounds going into
the feces, to the left of the compounds in the body. The rate constants connecting
the compartments also follow the symbolism from chapter one. In the above flow
chart, K, the summation of all the ways that X is removed from the body, is ku + kf
+ km while K1, the summation of all the ways that Xm is removed from the body,
is kmu +kmf.
Only those compartments are used which correspond to the drug’s pharmacoki-
netic description, thus when a drug is given by IV bolus and is 100% metabolized
with the metabolite being 100% excreted into the urine the model would look like
this:
Dose
km
kmu
Xm Xmu
Thus in this flow chart, K, the summation of all the ways that X is removed from
the body, is km while K1, the summation of all the ways that Xm is removed from
the body, is kmu.

Mathematics Review
Drugs sometimes are metabolized to two (or more) different metabolites. In the
first case, the drug is metabolized by two separate pathways resulting in this flow
chart:
Xmf1 kmf1 Xm1 kmu1 Xmu1
Dose
km1
kf X ku Xu
Xf
km2
kmf2 kmu2 Xmu2

Xmf2 Xm2
In this flow chart, K, the summation of all the ways that X is removed from the
body, is ku + kf + km1 + km2 while K1, the summation of all the ways that Xm1 is
removed from the body, is kmu1 +kmf1 and K3, the summation of all the ways
that Xm2 is removed from the body, is kmu2 + kmf2.
While in a second case, the drug is metabolized and the metabolite is further
metabolized resulting in this flow chart:
Dose
kf X ku Xu
Xf
km1
kmf1 kmu1
Xmf1 Xm1 Xmu1
km2
kmf2 kmu2 Xmu2

Xmf2 Xm2

Mathematics Review
In this flow chart, K, the summation of all the ways that X is removed from the
body, is ku + kf + km1 while K1, the summation of all the ways that Xm1 is
removed from the body, is kmu1 +kmf1+ km2 and K3, the summation of all the
ways that Xm2 is removed from the body is kmf2 + kmu2.
Both of these flow charts result in very different end equations, so it is imperative
that the flow charts accurately reflect the fate of the drug.
2.6.4 STEPS FOR INTEGRATION USING THE LAPLACE TRANSFORM

• Draw the model, connect the boxes with the arrows depicting where the drug goes.
• The building blocks of the differential rate equations are the arrows and what the tail touches.
• Write the differential rate equation for the box in question. The box is on the left side of the
equal sign and the building blocks are on the other. If the arrow goes away from the box, the
building block is negative, if it is going towards the box, the building block is positive.
• Take the LaPlace Transform of each side of the differential rate equation, using the table where
necessary.
• Algebraically manipulate the transformed equation until an equation having only one trans-
formed dependent variable on the left-hand side is obtained.
• Convert the transformed expression back to the time domain, using the table where necessary to
yield the Integrated equation.

Mathematics Review
2.6.5 EXAMPLE INTEGRATION USING THE LAPLACE TRANSFORM
Following an intravenous injection of a drug (bolus dose), its excretion may be

represented by the following pharmacokinetic scheme:
(Scheme I)
ku
X Xu
Where X is the mass of unchanged drug in the body at any time.
X u is the cumulative mass of unchanged drug in the urine up to any time, and k u is
the apparent first-order rate constant for excretion of unchanged drug.
Consider how the body excretes a drug
a. The building block is the arrow and what it touches. This first box (compart-
ment) of interest is [ X ] . The arrow ( k u) is going out, therefore, the rate is going out
and is negative, thus
dX
------- = –k u X (EQ 2-17)
dt
The negative sign indicates loss from the body.
Taking the LaPlace Transform of each side of equation 2-17:
sX – X0 = – k u X (EQ 2-18)
Note that because the independent variable (time) did not appear on the right-hand
side of equation 2-17, neither did the LaPlace Operator, s, appear there in equation
2-18. All that was necessary was to transform the dependent variable ( X ) into X .
Hence, the table was only required for transforming the left-hand side of equation
2-18.
Manipulating the transformed equation:
1. Get only one variable which changes with time (X)
2. Get X on the left and everything else on the right.

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sX + k u X = X0
X ( s + k u ) = X0
X0
X = ------------- (EQ 2-19)
s + ku
A
LetX0 = A Letk u = a X = ---------------- (EQ 2-20)
(s + a)
Note that X is the only transformed dependent variable and is on the left-hand side
of equation 2-19.
Converting back to the time domain:
–ku t
X = X0e (EQ 2-21)
A
Note that the right-hand side of equation 2-21 was analogous to ---------------- in the
(s + a)
table, because X0 is a constant (the initial dose administered). The left-hand side
of equation 2-21 could be converted back without the table.
The final expression is the familiar first-order integrated expression.

Mathematics Review
2.6.6 SECOND EXAMPLE INTEGRATION USING THE LAPLACE

TRANSFORM
Look at Scheme I again. Consider how the drug goes from the body into the urine.
The next box of interest is Xu . The arrow is coming in, therefore the rate is com-
ing in and is positive. thus,
dXu
--------- = k u X (EQ 2-22)
dt
(b) Taking the LaPlace Transform of each side of equation 2-22:
sX u – ( X u ) 0 = k u X (EQ 2-23)
But, at zero time, the cumulative mass of unchanged drug in the urine was zero:
that is ( Xu ) 0 = 0 .
sX u = k u X (EQ 2-24)
(c) Manipulating the transformed equation:
ku X
Xu = --------
- (EQ 2-25)
s
Note that there are two transformed dependent variables. One of them ( X ) can be
replaced by reference to equation 2-19.
ku X0
Xu = --------------------
- (EQ 2-26)
s(s + ku)
A
Let ( k u X0 ) = A Let ( k u ) = a X = ------------------- (EQ 2-27)
s(s + a)
(d) Converting back to the time domain:
–k t
kuX0 ⋅ ( 1 – e u )
X u = ----------------------------------------
ku

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Where k u X 0 and k u are analogous to “A” and “a” respectively in the table. Sim-
plifying,
– kut
Xu = X0 ( 1 – e ) (EQ 2-28)
2.6.7 THIRD EXAMPLE INTEGRATION USING THE LAPLACE TRANSFORM
During the intravenous infusion of a drug, its excretion may be represented by the
following pharmacokinetic scheme:
(Scheme II)
Infusion Q ku
X Xu
Where Q is the zero-order infusion rate constant (the drug is entering the body at a
constant rate and the rate of change of the mass of drug in the body is governed by
the drug entering the body by infusion and the drug leaving the body by excretion).
The drug entering the body does so at a constant (zero-order) rate.
dX
------- = Q – k u X (EQ 2-29)
dt
(b) Taking the LaPlace Transform of each side of equation 2-29:
Q
sX – X 0 = ---- – k u X
s
Note that because Q is a rate, and is therefore a function of the independent vari-
able (time), its transformation yields the LaPlace Operator. In this case, Q was
analogous to “A” in the table. But, at zero time, the mass of unchanged drug in the
body was zero: that is, X0 = 0
Q
sX = ---- – k u X (EQ 2-30)
s
(c) Manipulating the transformed equation:
Q
X = --------------------- (EQ 2-31)
s ( s + ku )

Mathematics Review
A
Let ( Q = A ) Let ( k u = a ) X = ------------------- (EQ 2-32)
s( s + a)
(d) Converting back to the time domain:

–k t
Q(1 – e u )
X = ----------------------------- (EQ 2-33)
ku
2.6.8 CONCLUSIONS
The final integrations (Eqs. 24, 24, and 28) are not the ultimate goal of pharmaco-
kinetics. From them come the concepts of:
1. (a) elimination half-life
1. (b) apparent volume of drug distribution
2. (c) plateau drug concentrations
These, and other concepts arising from still other equations, are clinically useful.
Once the method of LaPlace Transforms is mastered, it becomes easy to derive

equations given only the required pharmacokinetic scheme. Under such circum-
stances, it no longer becomes necessary to remember a multitude of equations,
many of which, though very similar, differ markedly in perhaps one minute detail.
As with any new technique, practice is required for its mastery. In this case, mas-
tery will banish the “calculus blues.”
It is also possible to see certain patterns which begin to emerge from the derivation
of the equations. For example, for a drug given by IV bolus the equation is
monoexponential, with the exponent being K, summation of all the ways that the
drug is removed form the body. A graph of the data (Cp v T on semi-log paper)
results in a straight line the slope of which is K, always. If the drug is entirely
metabolized K = km. If the drug is entirely excreted unchanged into the urine, K =
ku. If the drug is metabolized and excreted unchanged into the urine, K = km +ku.
thus K can have different meanings for different drugs, depending on how the
body removes the drug. Following the drug given by IV bolus a second example
of a pattern would be that of the data of the metabolite of the drug. From the
LaPlace, the equation for the plasma concentration of the metabolite of the drug
has in it K and K1, the summation of all the ways that the metabolite is removed
from the body, always. K1 would have different meanings depending on how the
metabolite is removed from the body.

Mathematics Review
After several years teaching, I was fortunate to have a resident rotate through our
pharmacokinetic site. She had come with a strong Pharmacokinetcs background
and during our initial meeting, she had told me that she had a copy of John Wag-
ner’s new textbook on pharmacokinetcs. She was excited that, finally, there was a
compilation of all the equations used in pharmacokinetics in one place.
“There are over 500 equations in the new book and I know every one,” she said.
“I’m not sure which one goes with which situation, though.” OOPS!
Throughout this text and on each exam, each equation is derived from first princi-
ples using scientific method, modeling and LaPlace Transforms in the hopes that
memorization will be minimized and thought (and consequently proper interpreta-
tion) would be maximized.

Mathematics Review
2.6.9 TABLE OF LAPLACE TRANSFORMS

A, B are constants
a, b, c are rate constants ( a ≠ b ≠ c )
s is the LaPlace Operator
x is a variable, dependent on time ( t )
m is a power constant
TABLE 2-17 Table of LaPlace Transforms
Time Function, F ( t ) LaPlace Transform, f ( s )
A A
---
s
At A-
---
2
s
At
m A ( m! -)
--------------
m+1
s
– at A-
Ae ----------
s+a
m – at A
At e --------------------------
-
m+1
(s + a)
– at A
A(1 – e ) -------------------
-------------------------- s (s + a )
a
– at A -
At (1 – e )
----- – A
-------------------------- --------------------
2
a a
2 s (s + a)
– at As – B-
– at B( 1 – e ) ------------------
Ae – -------------------------- s (s + a )
a
– at As – B -
A + B
---  ------------------ – Bt
1–e
----- --------------------
 a   a  a
2
s (s + a)

Mathematics Review
TABLE 2-17 Table of LaPlace Transforms
Time Function, F ( t ) LaPlace Transform, f ( s )
– bt – at A
A ( e – e )- --------------------------------
-
-------------------------------- (s + a)(s + b)
(a – b)
– bt – at A
A
----------------  1-----------------
– e -  -----------------
1 – e - -----------------------------------
-
(a – b)  b  –
a  s( s + a )( s + b )
 1 – e –bt  1 – e –at A
At- ----------------
A -------------------------------------
-
----- –  ------------------ –  ------------------ 2
s ( s + a) ( s + b)
ab ( a – b )  b2   a2 
1 – at – bt As – B -
---------------- [ ( B + Aa )e – ( B + Ab )e ] --------------------------------
( a – b) (s + a)(s + b)
As – B -
1  ( 1 – e –bt ) ( 1 – e – at )  -----------------------------------
---------------- – bt – at
A ( e – e ) – B  ---------------------- – ----------------------  s( s + a )( s + b )
(a – b)  b a 
  ( 1 – e –bt )  ( 1 – e – at ) As – B
1 B B Bt --------------------------------------
( a – b )  b   ----------------------
---------------- A + --
- ---------------------- – A + --
- – ------ 2
s ( s + a) ( s + b)
b  a  a ab
– ct – bt – at A
e e e -------------------------------------------------
-
A --------------------------------- + --------------------------------- + --------------------------------- (s + a)(s + b)(s + c)
(a – c)(b – c) (a – b )(c – b) (b – a )(c – a)
(1 – e ) (1 – e ) (1 – e ) ----------------------------------------------------
A ------------------------------------ + ------------------------------------- + ------------------------------------- s( s + a )( s + b )( s + c )
c( a – c )( b – c ) b( a – b)( c – b ) a( b – a )( c – a)
At- (1 – e ) ( 1 – e ) - --------------------------------------
(1 – e ) - ------------------------------------------------------
-
----- – A -------------------------------------- + -------------------------------------- + 2 2
bc 2 2 s ( s + a) ( s + b ) ( s + c )
c ( a – c) ( b – c ) b ( a – b) ( c – b) a ( b – a )( c – a)
dX
------- sX – X 0
dt
(m + 1 ) A
At -----
------------------- m
(m + 1) s

Mathematics Review
2.6.10 LAPLACE TRANSFORM PROBLEMS
By means of the LaPlace Transform, find the equation for:

1. The amount of drug in the body when the drug is given by IV Bolus (assume no metabolism).
2. The amount of drug in the urine when the drug is given by IV Bolus (assume no metabolism).
3. The amount of metabolite in the body when the drug is given by IV Bolus (assume no parent
drug excretion)
4. The amount of metabolite of the drug in the urine when the drug is given by IV Bolus (assume
no parent drug excretion)
5. The amount of metabolite of the drug in the urine when the drug is given by IV Bolus (assume
both parent drug and metabolite excretion)
6. The amount of drug in the body when the drug is given by IV infusion (assume no metabolism).
7. The amount of drug in the urine when the drug is given by IV infusion (assume no metabolism).
8. The amount of metabolite in the body when the drug is given by IV infusion (assume no parent
drug excretion).
9. The amount of metabolite in the urine when the drug is given by IV infusion (assume no parent
drug excretion).
10. The Rate of excretion of the metabolite into the urine for a drug given by IV bolus when
km+ku=kmu.
11. The amount of the principle metabolite (Xm1) when the drug is eliminated by several pathways
(Xu, Xm1,Xm2,Xm3,etc)
X
12. The concentration of drug, ------ , in the body when the drug is given orally by a delivery system
Vd
which is zero order. What is the concentration at equilibrium ( T ∞ ).
13. The amount of metabolite of a drug in the body when the drug is given by IV Bolus and con-
comitant IV infusion.
14. Disopyramide (D) is a cardiac antiarrythmic drug indicated for the suppression and prevention
of ectopic premature ventricular arrythmias and ventricular tachycardia. It appears that disopy-
ramide is metabolized by a single pathway to mono-dealkylated disopyramide (MND). In a
recent study, the pharmacokinetics of disopyramide were attempted to be elucidated by means
of a radioactive tracer. Since both D and MND would be labeled by the tracer, any equations
showing the time course of the label would show both the D and MND. By means of the
laPlace transform, find the equation for the rate of appearance of tracer into the urine if the drug
were given by IV Bolus.

Mathematics Review
2.6.11 LAPLACE TRANSFORM

SOLUTIONS
1. The amount of drug in the body when the drug is given
by IV bolus (assume no metabolism).
Dose
X ku Xu
X = Xo At time zero, all of the IV bolus is in the com-

partment.
Here K = ku
dX
------- = – k u X
dt
sX – X0 = –kuX
sX + kuX = X o
X ( s + k u )= Xo
Xo
X = -------------
s + ku
A
Let ( X0 ) = A , k u = a ,X = ----------------
(s + a)
– kut
X = Xo e

Mathematics Review
2. the amount of a drug in the urine when the drug is – kut

Xu= Xo ( 1 – e )
given by IV bolus (assume the drug is NOT metabolized
Dose
X ku Xu
NOTE: You must start where the drug is at time = 0.

Again K = ku
dX
------- = – k u X
dt
sX – X0 = –kuX
sX + kuX = X o
X ( s + k u )= Xo
Xo
X = ------------- You only need to go this far because you
s + ku
need to know X to put it in the equation for Xu. Thus:
dX
--------u- = k u X
dt
sX u – Xuo = k u X (Xuo = 0. No drug in urine at time = 0)
sX u = k u X Substituting from above for X.
X o ku
sX u = -----------------
-
(s + ku)
Xo ku
X u = --------------------
-
s(s + ku)
A
Let ( X0 k u ) = A , k u = a , X u = -------------------
s( s + a )
– kut
ku X o ( 1 – e )
X u = ------------------------------------
-
ku

Mathematics Review
3. the amount of metabolite of a drug in the body km X 0

when the drug is given by IV bolus (assume no parent sX m = -------------- – k mu Xm Substituting for X from above
drug excretion). s + km
km ⋅ Xo
X m = -----------------------------------------
-
( s + k mu ) ( s + k m )
Dose Let ( k m X 0 ) = A , k m = a = K , k mu = b = K1
A
X m = ---------------------------------
X (s + a)(s + b )
( km ⋅ X o ) –k t –k t
- ⋅ ( e mu – e m ) or
X m = ------------------------
km ( k m – k mu )
( km ⋅ Xo )
Xm kmu Xmu - ⋅ ( e – K 1t – e –K t ) in general terms.
X m = ---------------------
( K – K1 )
Remember: NOTE: We could also:

You must start where the drug is at time = 0. Let ( k m X 0 ) = A , k m = b , k mu = a
Here K = km and K1 = kmu
and then
dx
------ = – k m X
dt ( km ⋅ X o ) –k t –k t
X m = ------------------------- ⋅ ( e m – e mu ) or
( k mu – k m )
sX – Xo = – k m X
( km ⋅ Xo )
sX + k m X = Xo - ⋅ ( e – K t – e –K1t )
X m = ---------------------
( K1 – K )
X ( s + km ) = Xo Both of those equations are identical.
Xo
X = --------------
s + km
A
Let ( X0 ) = A , k m = a , X = ----------------
(s + a)
– kmt
X = Xo e
dX
---------m- = k m X – k mu X m
dt
sX m – Xm0 = k m X – kmu X m

Mathematics Review
4. the amount of metabolite of a drug in the urine X om = 0

when the drug is given by IV bolus (assume the parent
compound is not excreted). sX mu = k mu X m
Here, again, K = km and K1 = kmu
( k mu ) ( k m X o )
sX mu = -----------------------------------------
-
( s + k mu ) ( s + k m )
Dose
( k mu ) ( k m ) ( X o )
X mu = --------------------------------------------
-
s ( s + kmu ) ( s + k m )
X
k mu k m Xo  1 – e –kmt 1 – e –kmut
-  --------------------- – -----------------------
X mu = --------------------
k mu – k m  k m k mu 
km
Xm kmu Xmu
dXm
----------- = k m X – k mu X m
dt
sX m – Xom = k m X – kmu X m
sX m + k mu Xm = k m X
o X
substitute previously solved X = --------------
s + km
km Xo
X m ( s + k mu ) = --------------
s + km
km X o
X m = -----------------------------------------
-
( s + k mu ) ( s + k m )
– kmt – kmut
km Xo ( e –e )
X m = --------------------------------------------------
-
( k mu – k m )
dXmu
------------
- = k mu Xm
dt
sX mu – Xom = k muX m
Remember at time zero,

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5. the amount of metabolite of a drug excreted in dX mu

the urine when both the parent and metabolite are ------------- = k mu Xm
excreted.
dt
Here K = km + ku and K1 = kmu sX mu – Xom = k muX m = K1Xm
sX mu = K1X m
Dose
( k mu ) ( kmXo )
sX mu = --------------------------------------
( s + K1 ) ( s + K )
ku Xu
X ( k mu ) ( k m ) ( Xo )
X mu = ----------------------------------------
-
s ( s + K1 ) ( s + K )
km
k mu k m X o 1 – e – Kt 1 – e – K1t
X m u = ----------------------  ------------------- – ---------------------
K1 – K  K K1 
Xm kmu Xmu
dX
------- = – k u X – k m X
dt
sX – Xo = – k u X – k m X
sX + k u X + k m X = X o
X ( s + ku + km ) = Xo
( ku + km ) = K
Xo
X = ------------
s+K
– Kt
X = Xo e
dXm
------------ = k m X – k mu Xm = k m X – K1Xm
dt
sXm – X om = k m X – K1Xm
sX m + K1Xm = k m X
km Xo
X m = --------------------------------------
( s + K1 ) ( s + K )

Mathematics Review
6. The amount of drug in the body from a drug given by

IV infusion (assume no metabolism).
Q X ku Xu
At time zero, all the drug is still in the IV bag, therefore

there is no drug in the body. X0 = 0
Here K = ku
dX
------- = Q – k u X
dt
Q
sX – X0 = ---- – K u X
s
Q
sX + k u X = ----
s
Q
X = ---------------------
s ( s + ku )
Q –k t
X = ----- ( 1 – e u ) or X = Q
---- ( 1 – e –Kt )
ku K

Mathematics Review
7. the amount of drug in the urine when the drug is

given by infusion (assume the drug is NOT metabolized).
Q X ku Xu
Here K = ku
dX
------- = Q – k u X
dt
Q
sX – Xo = ---- – k u X
s
Q
sX + k u X = ----
s
Q
X ⋅ ( s + k u ) = ----
s
Q
X = -------------------------
s ⋅ (s + ku )
dX
--------u- = k u X
dt
sX u – Xo = k u X
sX u = k u X
ku Q
sX u = ------------------------
-
s ⋅ (s + ku)
ku Q
X u = ---------------------------
2
-
s ⋅ ( s + ku )
k u Qt  1 – e –kut
X u = ----------- – Qk u  -------------------
-
ku  k2  u
– kut – Kt
(1 – e ) (1 – e )
X u = Qt – Q ------------------------- or Xu = Qt – Q -----------------------
ku K

Mathematics Review
8. the amount of metabolite of a drug in the body – bt – at

X m = ----------------  ------------------ –  ------------------
A 1–e 1–e
from a drug given by IV infusion (assume no parent drug
excretion) Here K = km and K1 = kmu (a – b) b a
km Q  1 – e – k m t  1 – e – k mu t
X m = -------------------------  -------------------- –  --------------------- or
( k mu – k m )  k m   k mu 
Q X
k m Q  1 – e –Kt  1 – e –K1t
Xm = ---------------------
- ------------------ – ---------------------
( K1 – K )  K   K1 
km
Xm kmu Xmu
dX
------- = Q – k m X
dt
Q
sX – Xo = ---- – k m X
s
Q
sX + k m X = ----
s
Q
X ( s + k m ) = ----
s
Q
X = ----------------------
s ( s + km )
– kmt
(1 – e )
X = Q --------------------------
km
dX
---------m- = k m X – k mu X m
dt
sX m – Xo = k m X – k mu Xm
sX m = k m X – k mu Xm
km Q
X m = ---------------------------------------------
s ( s + k mu ) ( s + k m )

Mathematics Review
9. the amount of metabolite of a drug in the urine dX mu

from a drug given by IV infusion (assume that the parent ------------- = k mu Xm
compound is not excreted). Here K = km and K1 = kmu
dt
sX mu – Xomu = k mu X m substitute X m
k mu k m Q
Q X mu = ----------------------------------------------
2
-
X s ( s + k m ) ( s + k mu )
k mu k m Qt k mu k m Q  ( 1 – e –kmut ) ( 1 – e – k mt )
km X mu = ---------------------- –  ---------------------  ----------------------------- – -------------------------- or
k m ⋅ k mu  k m – k m u  k
2
k
2

mu m
Xm kmu Xmu k mu k m Qt k mu k m Q  ( 1 – e –Kt ) ( 1 – e –K1t )

X mu = ---------------------- –  --------------------  ------------------------ – --------------------------
K1 ⋅ K  K1 – K   2 2

K K1
dX
------- = Q – k m X
dt
Q
sX – Xo = ---- – k m X
s
Q
sX + k m X = ----
s
Q
X ( s + k m ) = ----
s
Q
X = ----------------------
s ( s + km )
dX
---------m- = k m X – k mu X m
dt
sX m – Xo = k m X – k mu Xm
sX m + k mu X m = k m X
km Q
X m ( s + k mu ) = ----------------------
s ( s + km )
km Q
X m = ---------------------------------------------
s ( s + k m ) ( s + k mu )
k m Q  1 – e –kmut  1 – e –kmt
X m = --------------------  ----------------------- – ---------------------
k m – k mu  k mu   k m 

Mathematics Review
10. the rate of excretion of the metabolite into the dX m

urine for a drug given by IV bolus when ---------- = ( k m X – k muX m )
dt
k m + k u = k mu
sX m – Xom = ( k m X – K1Xm )
In this case, K = ku +km and K1 = kmu and thus K = K1.
This is not normal but could happen. The problem arises sX m + K1X m = k m X
when we get to the LaPlace that assumes the rate con-
stants are different (i.e. a ≠ b ) because for this special km X o
case a = b . X m ( s + K1 ) = ------------
s+K
km Xo
X m = -------------------------------------- (remember- K1 = K)
( s + K ) ( s + K1 )
Dose
km Xo
X m = ------------------------------------------
( s + K1 ) ( s + K1 )
ku Xu km Xo
X
X m = ----------------------2- (kmX0 = A)
( s + K1 )
km
– K1t
X m = k m Xo te
Xm kmu Xmu dX mu
------------
- = k mu Xm
dt
dX mu
dX
. ------- = – k u X – k m X - = k mu k m Xo te –K1t
------------
dt dt
X ( s + ku + km ) = Xo
Xo
X = -------------------------------
( s + k u + km )
K = ( ku + km )
k mu = K1
Xo
X = ----------------
-
(s + K)
– Kt
X = Xo e

Mathematics Review
11. the principal metabolite ( X m1 ) when the drug is k m1 Xo

cleared by several pathways ( X u, X m 1, X m 2 ) X m1 ( s + K1 ) = ----------------
-
(s + K)
In this case K = km1 + km2 + ku, K1 = kmu1 and K2 = k m1 X o
kmu2 X m1 = --------------------------------------
( s + K1 ) ( s + K )
k m1 Xo – K1t –Kt
-(e
X m1 = ---------------- –e )
K – K1
Xm1 kmu1 Xmu1
Dose
km1
X ku Xu
km2
kmu2 Xmu2
Xm2
dX
------- = – k u X – k m1 X – k m2 X
dt
sX – Xo = – k u X – k m1 X – k m2 X
sX + k u X + k m1 X + km2 X = Xo
X ( s + k u + k m1 + k m2 ) = Xo Let K = ku + km1 + km2
Xo
X = ----------------
-
(s + K)
K = ( k u + k m1 + k m2 ) and K1 = k mu1
dXm1
------------
- = k m1 X – K1X m1
dt
sX m1 – Xm1o = k m1 X – K1X m1
X m1o = 0
k m1 Xo
sX m1 + K1X m1 = ----------------
-
(s + K)

Mathematics Review
12. the concentration of drug X ⁄ Vd in the body k a Q  ( 1 – e –Kt ) ( 1 – e –kat ) 

( k a – K ) 
when the drug is given orally by a delivery system which - ------------------------ – ------------------------- 
X = -------------------
is zero order. What is the concentration in the body at K ka 
equilibrium ( t ∞ )
 1 – e –Kt ) ( 1 – e –kat ) 
-  (-----------------------
ka Q
Here K = ku C = -------------------------- - – ------------------------- 
( k a – K )Vd  K ka 
Q Xa ka X ku Xu k Q
1- ----
1  
If t= ∞ , then e –kt = 0 , thus C = --------------------------
a
-  --- – -
( k a – K )Vd  K ka 
Q
simplified yields: C = ----------
-
KVd
dX
--------a- = Q – k a X a
dt
Q
sX a – Xao = ---- – k a Xa
s
X a0 = 0
sX a + k a Xa = ( Q ⁄ s )
X a ( s + ka ) = ( Q ⁄ s )
Q
X a = ---------------------
s(s + ka)
– kat
Q( 1 – e )
X a = -----------------------------
ka
dX
------- = k a X a – KX
dt
sX – Xo = k a Xa – KX
Xo= 0
ka Q
sX + KX = ---------------------
s ( s + ka )
ka Q
X ( s + K ) = --------------------
-
s ( s + ka )
ka Q
X = --------------------------------------
-
s ( s + ka ) ( s + K )

Mathematics Review
13 the metabolite of a drug in the body Xm given

k m Q  ( 1 – e –K1t ) ( 1 – e –Kt ) 
( K – K1 ) 
by IV infusion and concomitant IV bolus dose. - -------------------------- – ----------------------- 
X m = ---------------------
K1 K 
Infusion:
Here K = km and K1 = kmu IV Bolus:
dX
------- = – KX
dt
Dose
sX – Xo = – KX
Q sX + KX = X o
X
X ( s + K )= Xo
km
Xo
X = -----------
-
s+K
Xm kmu Xmu
dX m
---------- = k m X – K1X m
dt
dX sX m – Xo = k m X – K1X m
------- = Q – KX
dt
Q sX m + K1X m = k m X
sX – Xo = ---- – KX
s
km X o
X m ( s + K1 ) = ------------
Q s+K
sX + KX = ----
s
km Xo
Q X m = --------------------------------------
X ( s + K ) = ---- ( s + K1 ) ( s + K )
s
km Xo – Kt – K 1t
Q -(e – e
X m = --------------------- )
X = -------------------- ( K1 – K )
s( s + K )
Thus,
dX
---------m- = k m X – K1X m km X o
X m =  ---------------------- ( e – e
dt – Kt – K 1t 
) + …
( K1 – K )
sX m – Xo = k m X – K1Xm
 k m Q  ( 1 – e –Kt ) ( 1 – e –K1t ) 
sX m + K1X m = k m X  -----------------  ----------------------- – -------------------------- 
 K1 – K  K K1 
km Q
X m ( s + K1 ) = -------------------
-
s( s + K )
km Q
X m = ----------------------------------------
-
s ( s + K1 ) ( s + K )

Mathematics Review
14. By means of the LaPlace transform, find the km X o

equation for the rate of appearance of the tracer in the X m ( s + K1 ) = -----------
-
urine if the drug were given by IV bolus.
s+K
Here K = ku + km and K1 = kmu km Xo

X m = --------------------------------------
( s + K ) ( s + K1 )
Dose km Xo
- { e –K1t – e –Kt }
X m = ---------------------
( K – K1 )
ku Xu dX mu k mu k m Xo –K1t – Kt
X -{e
------------- = k mu Xm = --------------------- –e }
dt ( K – K1 )
dX dX mu  k mu k m X o
- = k u ( X o e ) +  ---------------------
- { e – e }
– Kt –K1t – Kt
km --------u- + ------------
dt dt   ( K – K1 ) 
Xm kmu Xmu
dX
------- = – k u X – k m X
dt
X ( s + ku + km ) = Xo
( ku + km ) = K
Xo
X = -----------------
(s + K)
– Kt
X = Xo e
dX
--------u- = k m X = k u ( Xo e –Kt )
dt
dX
---------m- = k m X – K1X m
dt
sX m – Xo = k m X – k1Xm
km Xo
sX m + K1X m = ----------------
-
(s + K)

CHAPTER 3 Pharmacological Response

OBJECTIVES
After completing this chapter, the student will be able to:
1. Given patient data of the following types, the student will be able to properly con-
struct (III) a graph and compute (III) the slope using linear regression: response
(R) vs. concentration (C), response (R) vs. time (T), concentration (C) vs. time (T)
2. Given any two of the above data sets, the student will be able to compute (III) the
slope of the third by linear regression.
3. Give response vs. time and response versus concentration data, the student will be
able to compute (III) the terminal (elimination) rate constant and half life of the
drug.

Pharmacological Response
3.1 Pharmacological Response

Drug must get into blood One theory (A.J. Clarke) on the mechanism of action of drugs is the occupation
and blood is in contact theory. It suggests that the intensity of a pharmacological response (E) is propor-
with receptor. tional to the concentration of a reversible drug-receptor complex
3.1.1 THE HYPERBOLIC RESPONSE EQUATION

A mathematical description of the occupation theory, assuming complete and
instantaneous drug distribution, yields
[ D ]E max
E = ---------------------
- (EQ 4-34)
KR + [D ]
where E is the intensity of the pharmacological response, Emax is the maximum

1.0
PKAnalyst Plot attainable value of E , [ D ] is the molar concentration of free drug at the active com-
0.8
plex and K R is the dissociation constant of the drug-receptor complex.
0.6
If E is plotted against [D] a hyperbolic curve will result; the asymptote will be
E
0.4
0.2
E max .
0.0
0.0 0.8 1.6 2.4 3.2 4.0
D
a. If linear pharmacokinetics hold, the molar concentration of free drug at the
active site is proportional to the plasma concentration of the drug once equilibrium
has been established. Hence, a plot of E against Cp will also be hyperbolic.
b. Because the mass of drug in the body is X = V ⋅ Cp , a plot of E against X will be

hyperbolic.
c. For a series of doses the value of X at the same given time after dosing is propor-
tional to the dose (D). Thus, a plot of E against D will also be hyperbolic at a spe-
cific time.
1.0 d. Any hyperbolic curve, if plotted on reverse semilogarithmic paper (i.e.,

0.8 abscissa is logarithmic), has a sigmoid shape. If we plot E against Cp (of X , or D )
0.6
in this manner, the plot is virtually linear in the range E ⁄ E max = 0.2 → 0.8 ; and if
Response
0.4
0.2 this is the clinical range of responses, linear equations may be written. For exam-
0.0 ple,
10 -810-710 -610-510 -410-310-210-1
Conc. E = m ⋅ ln x + b (EQ 4-35)
where m is the slope

Plot of Response vs. This example equation shows that, in the clinical range, the intensity of a pharma-
Ln(C) is a straight line in cological response is proportional to the logarithm of the administered dose, pro-
the middle (if you viding response is measured at a consistent time after dosing. The proportionality
squint), but only
between 20% and 80%
constant (slope, m ) is a function of the affinity of the drug for the receptor. In fact,
maximum response equation 4-35 yields a log-dose response plot. Note that doubling the dose does not
double the response.
3.1.2 INTERRELATIONSHIPS BETWEEN CONCENTRATION, TIME AND

RESPONSE
Pharmacological Response (R), Concentration (C), and Time (t) are interrelated.
The response and concentration relationship is studied in pharmacology. The con-
centration and time relationship is studied in pharmacokinetics. The response and
time relationship is applied in therapeutics.
Remember: Use only You should know what the various graphical relationships look like. Response vs.
the data between 20% natural log of concentration is sigmoidal. (S shaped). We are interested in the mid-
and 80% of maximum dle almost straight part. The slope is dR ⁄ d ln c .
response for the straight
part of both response
vs. Ln(c) and response Response vs. time is a straight line. The slope is dR ⁄ dt .
vs. t.
Natural log of concentration vs. time (drug given by IV bolus) is a straight line.
The slope is d ln c ⁄ dt .
You should be able to obtain the slope of each of these relationships from data sets.
You should be able to obtain the third slope’s relationship given the other two (or
data sets with which to get the other two).
dR dR- d----------
ln c- (EQ 4-36)
------- = ---------- ⋅
dt d ln c dt
dR - dR ⁄ dt
---------- = -------------------- (EQ 4-37)
d ln c d ln c ⁄ dt
d----------
ln c- dR ⁄ dt
= ---------------------- (EQ 4-38)
dt dR ⁄ d ln c
NOTE: Only between You should be able to apply the equation y = mx + b to each of the above relation-
20% and 80% of maxi- ships. Given the slope (or having obtained the slope) and two of the three variables
mum response!!!!!! (y, x, b), you should be able to find the third.

3.2 Change in Response with Time
3.2.1 ONE-COMPARTMENT OPEN MODEL: INTRAVENOUS BOLUS

INJECTION
– Kt – Kt
X = X0 e = De (EQ 4-39)
or
Ln ( X ) = Ln ( D ) – Kt (EQ 4-40)
Substituting twice from eq. 4-35 once at time t and once at zero time
E – b- E 0–b
----------- = --------------- – Kt → E = E0 – Rt (EQ 4-41)
m m
Hence a plot of the intensity of the pharmacological response at any time ( E )

against time declines linearly. The slope is –R = ( –K ⋅ m ) and the intercept is E0 (the
initial intensity).
3.2.2 ONE-COMPARTMENT OPEN MODEL: ORAL ADMINISTRATION

Response follows Because E is proportional to ln x at any time, a plot of E against t will be analo-
plasma profile. gous to a plot of ln x against t . Hence E will rise at first and then decline with time.
When t is large, the terminal slope will be –R .
3.2.3 DURATION OF EFFECTIVE PHARMACOLOGICAL RESPONSE ( t dur )

Duration of action is Once equilibrium has been established, there is a minimum plasma concentration
related to how long below which no pharmacological response is seen; this concentration is ( C p ) eff or
plasma concentration is
above Minimum Effec- MEC . For an intravenous bolus injection, the time to reach ( C p ) eff is t dur .
tive Concentration.
– Ktd ur
( C p )eff = ( C p ) 0 e multiplying by the volume of distribution we obtain
ln ( X eff ) = ln ( D ) – Kt dur (EQ 4-42)
Rearranging,

ln  --------
D
X eff
t dur = -------------------- (EQ 4-43)
K
The duration of effective pharmacological response is proportional to the (natural)

logarithm of the dose. A second rearangement of equation 4-42 results in :
ln ( Dose ) ln ( Xeff )
t dur = ----------------------- – ------------------
- (EQ 4-44)
K K
Thus a plot of duration of action vs ln dose would result in a straight line with a
ln ( X ef f )
slope of 1/K and an x intercept of – ------------------- .
K
3.2.4 PHARMACOKINETIC PARAMETERS FROM RESPONSE DATA

How can I get the elimi- The measurement of pharmacological effect provides a non-invasive means of
nation rate constant obtaining the value of t 1 ⁄ 2 (but not V ).
from pharmacological
data? Use this “cook-
book.” a. Obtain a log dose-response plot (Eq. 4-37). The response must always be mea-
sured at the same time after administering the dose.
Remember: Use only b. Find the slope (m) of this plot.
the data between 20%
and 80% of maximum c. Obtain a response against time plot for a single dose (Eq. 4-36).
Response for both of
these plots.
d. Find the terminal slope ( –R ) of this plot.
R
e. Calculate K = ---- .
m
t 1 ⁄ 2 =  -------------
0.693
f. Calculate  K 
.
3.2.5 “DELAYED” RESPONSE

Two compartment If a drug does not distribute instantaneously to all the body tissues (including the
model - biophase is in active site), the pharmacological response will not always parallel the drug con-
second compartment. centrations in the plasma. In such a situation the response may parallel the mass of
drug presumed to be in a second compartment ( X 2 ) , and hence seem “delayed”.
Eventually, however, once equilibrium is attained, the response will parallel
plasma concentrations. In such a case, E is proportional to ln X 2 .

Thus a plot of E against X1 (or E against Cp ) will show a hysteresis loop with time,
most noticeably during an intravenous infusion.
3.2.6 RESPONSE OF ACTIVE METABOLITE:

Parent compound (inac- In the case of an inactive prodrug yielding an active metabolite, the response
tive) yields active curves will mirror the active metabolite plasma profile (assuming the biophase is
daughter compound. the plasma) and not the prodrug plasma profile.

3.3 Therapeutic Drug Monitoring

Part of Pharmaceutical The pharmacokinetics of a drug determine the blood concentration achieved from
Care! a prescribed dosing regimen. During multiple drug dosing, the blood concentration
will reflect the drug concentration at the receptor site; and it is the receptor site
concentration that determines the intensity of the drug’s effect. Therefore, in order
to predict a patient’s response to a drug regimen, both the pharmacokinetics and
pharmacological response characteristics of the drug must be understood. Phar-
macological response is closely related to drug concentration at the site of action.
We can measure plasma concentration and assume that the site of action is in rapid
equilibrium with the plasma since we usually do not measure drug concentration in
the tissue or at the receptor site. This assumption is called “kinetic homogeneity”
and is the basis for clinical pharmacokinetics.
Need to keep plasma There exists a fundamental relationship between drug pharmacokinetics and phar-
concentration in the macologic response. The relationship between response and ln-concentration is
therapeutic range to sigmoidal. A threshold concentration of drug must be attained before any response
optimize therapy.
is elicited at all. Therapy is achieved when the desired effect is attained because
the required concentration has been reached. That concentration would set the
lower limit of utility of the drug, and is called the Minimum Effective Concentra-
tion (MEC). Most drugs are not “clean”, that is exhibit only the desired therapeu-
tic response. They may also exhibit undesired side effects, sometimes called toxic
effects at a higher, (hopefully a lot higher), concentration. At some concentration,
these toxic side effects become become intolerable/and or dangerous to the
patient.. That concentration, or one below it, would set the upper limit of utility
for the drug and is called the Maximum Therapeutic Concentration or Minimum
Toxic Concentration (MTC). Patient studies have generated upper (MTC) and
lower (MEC) plasma concentration ranges that are deemed safe and effective in
treating specific disease states. These concentrations are known as the “therapeutic
range” for the drug (Table 4-18).
When digoxin is administered at a fixed dosage to numerous subjects, the blood

concentrations achieved vary greatly. Clinically, digoxin concentrations below 0.8
ng ⁄ ml will elicit a subtherapeutic effect. Alternatively, when the digoxin concen-
tration exceeds 2.0 ng ⁄ ml side effects occur (nausea and vomiting, abdominal pain,
visual disturbances). Drugs like digoxin possess a narrow therapeutic index
because the concentrations that may produce toxic effects are close to those

required for therapeutic effects. The importance of considering both pharmacoki-

netics and pharmacodynamics is clear.
TABLE 4-18 Average therapeutic drug concentration
DRUG RANGE
digoxin 0.8-2.0 ng ⁄ ml
gentamicin 2-10 µg ⁄ ml l
lidocaine 1-4 µg ⁄ ml
lithium 0.4-1.4 mEq ⁄ L
phenytoin 10-20 µg ⁄ ml
phenobarbitol 10-30 µg ⁄ ml
procainamide 4-8 µg ⁄ ml
quinidine 3-6 µg ⁄ ml
theophylline 10-20 µg ⁄ ml
Note that drug concentrations may be expressed by a variety of units.
Pharmacokinetic factors that cause variability in plasma drug concentration are:

• drug-drug interactions
• patient disease state
• physiological states such as age, weight, sex
• drug absorption variation
• differences in the ability of a patient to metabolize and eliminate the drug
If we were to give an identical dose of drug to a large group of patients and then
measure the highest plasma drug concentration we would see that due to individual
variability, the resulting plasma drug concentrations differ. This variability can be
attributed to factors influencing drug absorption, distribution, metabolism, and
excretion. Therefore, drug dosage regimens must take into account any disease
altering state or physiological difference in the individual.
Therapeutic drug monitoring optimizes a patient’s drug therapy by determining

plasma drug concentrations to ensure the rapid and safe drug level in the therapeu-
tic range.
Two components make • Assays for determination of the drug concentration in plasma
up the process of • Interpretation and application of the resulting concentration data to develop a safe and effective
therapeutic drug drug regimen.
monitoring:

The major potential advantages of therapeutic drug monitoring are the maximiza-
tion of therapeutic drug benefits and the minimization of toxic drug effects. The
formulation of drug therapy regimens by therapeutic drug monitoring involves a
process for reaching dosage decisions.

3.3.1 THERAPEUTIC MONITORING: WHY DO WE CARE?

The usefulness of a drug’s concentration vs. time profile is based on the observa-
tion that for many drugs there is a relationship between plasma concentration and
therapeutic response. There is a drug concentration below which the drug is inef-
fective, the Minimum Effective Concentration (MEC), and above which the drug
has untoward effects, the Minimum Toxic Concentration (MTC). That defines the
range in which we must attempt to keep the drug concentration (Therapeutic
Range).
The data in Table 4-18 are population averages. Most people respond to drug con-
centrations in these ranges. There is always the possibility that the range will be
different in an individual patient.
For every pharmacokinetic parameter that we measure, there is a population aver-

age and a range. This is normal and is called biological variation. People are differ-
ent. In addition to biological variation there is always error in the laboratory assays
that we use to measure the parameters and error in the time we take the sample.
Even with these errors, in many cases, the therapy is better when we attempt to
monitor the patient’s plasma concentration to optimize therapy than if we don’t.
This is called therapeutic monitoring. If done properly, the plasma concentrations
are rapidly attained and maintained within the therapeutic range throughout the
course of therapy. This is not to say all drugs should be monitored. Some drugs
have a such a wide therapeutic range or little to no toxic effects that the concentra-
tions matter very little. Therapeutic monitoring is useful when:
• a correlation exists between response and concentration,
• the drug has a narrow therapeutic range,
• the pharmacological response is not easily assessed, and
• there is a wide inter-subject range in plasma concentrations for a given dose.
In this era of DRGs, where reimbursement is no longer tied to cost, therapeutic

monitoring of key drugs can be economically beneficial to an institution. A recent
study (DeStache 1990) showed a significant difference with regard to length of
stay in the hospital between the patients on gentamicin who were monitored (and
their dosage regulated as a consequence) vs. those who were not. With DRGs the
hospital was reimbursed a flat fee irrespective of the number of days the patient
stayed in the hospital. If the number of days cost less than what the DRG paid, the
hospital makes money. If the days cost more than the hospital loses money. This
study showed that if all patients in the hospital who were on gentamicin were mon-
itored, the hospital would save $4,000,000. That’s right FOUR MILLION per year.
I would say that would pay my salary, with a little left over, and that is only one
drug!

The process of • First the MD must order the blood assays.

therapeutic monitoring • Second, someone (nurse, med tech, you) must take the blood.
takes effort.
• Someone (lab tech, you) must assay the drug concentration in the blood.
• You must interpret the data.
• You must communicate your interpretation and your recommendations for dosage regimen
change to the MD. This will allow for informed dosage decisions.
• You must follow through to ensure proper changes have been made.
• You must continue the process throughout therapy. Therapeutic drug monitoring, in many cases,
will be part of your practice. It can be very rewarding.
Thus, if we have determined the therapeutic range, we could use pharmacokinetics

to determine the optimum dosage regimen to maintain the patient’s plasma con-
centration within that range.
Selected References
1. Nagashima, R., O’Reilly, RA., and Levy, G, Kinetics of pharmacologic effects in man: the anticoagulant action of warfarin. Clin.
Pharm. Therap, 10 22-35 (1969).
Remember: We want the straight part!

2. Wagner, J.G, Relations between drug concentration and response. J. Mond. Pharm., 4, 279-310 (1971).
3. Gibaldi M. and Levy, G. Dose-dependent decline of pharmacologic effects of drugs with linear pharmacokinetics characteristics.
J.Pharm.Sci, 61, 567-569 (1972).
4. Brunner, L., Imhof, P., and Jack, D. Relation between plasma concentrations and cardiovascular effects of oral oxprenolol in
man. Europ. J. Clin. Pharmacol., 8, 3-9 (1975).
5. Galeazzi, R.L., Benet, L.Z., and Sheiner, L.B. Relationship between the pharmacokinetics and pharmacodynamics of procaina-
mide. Clin. Pharm. Therap., 20, 67-681 (1976).
6. Joubert, P., et al. Correlation between electrocardiographic changes, serum digoxin, and total body digoxin content. Clin.
Pharm. Therap., 20, 676-681 (1976).
7. Amery, A., et al. Relationship between blood level of atenolol and pharmacologic effect. Clin. Pharm. Therap., 21, 691-699
(1977).

3.4 Problems
What to do.---> We want to get pharmacokinetic data (elimination rate con-
stant) from pharmacological response data (Response vs concontration and
Response vs time graphs) .
Response vs Time Graph

1. Plot Response vs Time on Cartesian (regular) Graph Paper.
1.0 13. Use Response data between 20 and 80 percent of maximum (Pick the straight part) to do the lin-
ear regression on. (Rule of thumb: Connect first and last data point with a straight line. If all
0.8
the points fall on one side of the line, its not straight!
Response
0.6
dR
14. Find the slope of the straight line, ------- , (eyeball the rise over the run or use linear regression as
0.4 dT
0.2
required). Important: you must determine the best fit line through all of the points that you will
use. Eyeball method: Get the line as close to the points as possible placing as many points
0.0
10 10 10 10 10 10
above the line as below the line. Take two points on the line (not data points) to calculate the
Time
change in Y over the change in X.
Response vs Ln(Concentration) Graph

1. Turn semi-log paper on its side so that the numbers are on the top.
10010
10010
10 10
1
1.0
10
0.8
0
0.6
Response
0.4
0.2
Response
0.0
1010
10-810-710-610-510 -410-310 -210-1
Conc.
1
Concentration
1
10
0 1
What we are attempting to do is get the logarithm part of the paper on the x axis and have the
numbers get bigger as you go from left to right.
15. Plot concentration on the x axis and response on the y.
16. Find the slope of the line plotted this way by the rise over the run method.
Run is change in ln(C).
If you take any two concentrations such that C2 = 2*C1 then the run is (ln(C2) - ln(C1)).
Using rules of logs, when two logs are subtracted, the numbers are devided, thus: = ln(C2/C1).
If C2 = 2*C1 then ln(C2/C1) = ln(2) = 0.693.

Rise = change in Response.

Take the difference of the two responses coresponding to the concentrations picked. (R2-R1).
rise 2 1 R –R
17. The slope of the line is m = -------- = -----------------
-
run 0.693
Ln(Concentration) vs Time Graph (Pharmacokinetic Data)
If you have concentration vs Time data:

1. Plot Concentration vs time on semi-log paper (Y axis is concentration this time)
100
10
Concentration
1010
110
0 1
Time
18. Find the slope as before, using semi log paper (Remeber the log is on the Y axis this time, so
you find two concentrations such that c2 = 2*c1 and put it in the rise this time. Thus the slop of
rise 0.693 0.693
the line is m = -------- = -------------- = ------------- = – k
run t2 – t1 –t1
---
2
If you have pharmacological response data:

1. Divide the slope of the Response vs Time graph by the slope of the Response vs ln(C) graph:
dR
-------
slope of r vs t dT dln(C)
------------------------------------------ = --------------- = --------------- = m = – k
slope of r vs ln(c) dR -
-------------- dT
dln(C)
Both methods should be equivalent.
Additional problems are available in chapter 14, practice exams.

3.5 Oxpranolol
Brunner et al, Europ. J. Clin. Pharmacol., 8, 3-9 (1975).
In humans, the pharmacological response to oxpranolol (a beta blocker) is a decrease in beats per minute (bpm) com-
pared to placebo during physical exercise. The following approximate mean data is from 7 healthy volunteers: beats per
minute (bpm) altered with time (t) after oral administration of three doses (D).
TABLE 4-19
Response vs Response vs
Concentration time
BPM Dose (mg) BPM Time (hr)

10 40 17.6 1
13.5 60 13.9 2
16 80 10.2 3
19 120 6.6 4
21 160
TABLE 4-20 Oxpranolol plasma concentration following 160 mg IV dose
C p  ------
ng
Time (min) ml
30 699
60 622
120 413
150 292
240 152
360 60
480 24
1. Calculate the half life ( t 1 ⁄ 2 ) of oxpranolol from the pharmacological response table.
2. Plot plasma concentration data on Cartesian graph paper directly as well as transforming Cp into ln C p .
3. Plot plasma concentration data on semilog paper. Use linear regression to find the rate constant of elimination of
oxpranolol.
4. Calculate the half life obtained from the concentration data and compare it with the half life calculation based on the
pharmacological response.

Minoxidil (Problem 4 - 1)
Shen et al. Clin. Pcol. Ther 17:593-8 (1975)
Minoxidil is a potent antihypertensive which lowers the mean arterial blood pressure (MAP) in certain patients.
PROBLEM TABLE 4 - 2. Minoxidil
Initial decrease in MAP ( mmHg ) Dose ( mg )

17 2.5
40 5.0
53 7.5
63 10.0
76 15
PROBLEM TABLE 4 - 3. Minoxidil
25 mg I.V. Bolus yielded:
Decrease in MAP ( mmHg ) Time ( hr )

75 20
66 30
56 40
48 50
From the preceding information, determine the following:
dR
1. Graph and find ------------ (slope of (R)esponse vs. ln(C)oncentration graph).
d ln C
dR
2. Graph and find ------- (slope of (R)esponse vs. (T)ime graph).
dt
dR
-------
dt
3. Find the ln(C)oncentration vs. (T)ime slope : ------------- : Note that your slope m = – K . If you are having problems
dR
------------
d ln C
understanding this, refer to Sections 2.4.2 -2.4.4. K is the elimination rate constant.
4. Calculate t 1 ⁄ 2 =  0.693
-------------  .
K 

Propranolol (Problem 4 - 4)
Citation?
Beta blockers can be considered first line drugs of choice in the treatment of hypertension in certain patients. The fol-
lowing data was obtained regarding Propranolol used to treat hypertension in a group of patients.
PROBLEM TABLE 4 - 5. Propranolol
Fall in Systolic BP (mmHg) Cp
20 50
16 40
11 30
5 20
PROBLEM TABLE 4 - 6. Propranolol
I.V. Bolus dose of Propranolol
Fall in Systolic BP (mmHg) Time (hr)

24 1
20 2
19 3
9 6
From the preceding information, determine the following:
dR
1. Graph and find ------------ (slope of (R)esponse vs. ln(C)oncentration graph).
d ln C
dR
dt
dR
-------
dt
3. Find the ln(C)oncentration vs. (T)ime slope : ------------- : Note that your slope m = – K . If you are having problems
dR
------------
d ln C
understanding this, refer to Sections 2.4.2 -2.4.4.
4. Calculate t 1 ⁄ 2 =  0.693
-------------  .
K 

3.5.1 ANSWERS: OXPRANOLOL

1. Calculate the half life ( t 1 ⁄ 2 ) of oxpranolol from the pharmacological response table
Oxpranolol
22
20
Response (BPM)
18
16
14
12
10
1 2 3
10 10 10
Dose (mg)
TABLE 5.
X Y 2
ln(Dose) Dose Response X X⋅Y
3.689 40 10 13.61 36.89
4.094 60 13.5 16.76 55.27
4.382 80 16 19.20 70.11
4.787 120 19 22.92 90.96
5.075 160 21 25.75 106.58
ΣX = 22.03 ΣY = 79.5 2
ΣX = 98.25 ΣXY = 359.82
2
( ΣX ) = 485.23
ΣX Σy
)
X = --------- = 4.41 y = ------ = 15.9

n n
( Σ(x) ⋅ Σ(y )) – (n ⋅ Σ(x ⋅ y))

m = ---------------------------------------------------------------------
2 2
Slope of the line from linear regression. Chapter 2.4.4
[Σ(x) ] – ( n ⋅ Σ (x ))
( 22.03 ⋅ 79.5 ) – ( 5 ⋅ 359.82 )

m = -------------------------------------------------------------------- = 7.93
485.32 – ( 5 ⋅ 98.25 )

dR -
---------- = 7.93 the slope is equal to the linear regression of the change in response vs. ln concentration.
d ln c
OXPRANOLOL
18
16
Response (BPM)
14
12
10
6
1.0 1.5 2.0 2.5 3.0 3.5 4.0
Time (hr)
1 R –R 2 16 – 10 dR
The slope of this plot is m = ------------------ = --------------------------- = – 3.71 therefore, ------- = – 3.71 .
T1 – T 2 1.45 – 3.07 dt
dR
-------
dt d ln c –3.71 –1 ln 2 0.693 -
----------- = ----------- = – k = ------------- = – 0.4678hr t 1 ⁄ 2 = -------- = -------------------------- = 1.48hr half life (89 min).
dR dt 7.93 k –1
----------- 0.4678hr
d ln c
2. Plot plasma concentration data on Cartesian graph paper directly as well as transforming Cp into ln C p .

Plasma concentration vs. Time

800 Oxpranolol
3
10
640
Concentration (ng/mL)
480
2
10
320
Concentration (ng/ml)
160
1
10
0 0 100 200 300 400 500
0 100 200 300 400 500
Time (min)
Time (min)
3. Plot plasma concentration data on semilog paper. Use linear regression to find the rate constant of elimination of
oxpranolol.
Using linear regression, as described above, the elimination rate constant is approximately
0.007797 min-1 * (60 min/hr) = 0.4678 hr-1

4. Calculate the half life obtained from the concentration data and compare it with the half life calculation based on the
pharmacological response.
0.693
t 1 ⁄ 2 = ------------------- = 90min = 1.5 hrs compared to 1.48 hours (89 min) from the pharmacological response
0.00763
method.

3.5.2 ANSWERS: MINOXIDIL
NOTE: Answers will vary depending on whether linear regression is calculated

via calculator or using the formula such as observed in Problem 1. Either method
can be used. However, if you use the formula, you should be within 10% of the
calculated answer. A word of caution: if you choose to do linear regression via
calculator make sure you have valid data. This cannot be assured until you have
graphed all the data points given. Many a student has incorrectly calculated
parameters because he/she falsely assumes that all the points are valid. Blindly
choosing data points for linear regression will only lead to error. Every problem
in this manual has been derived from actual journal articles and will therefore be
“real” data. This real-world data is inexact.
dR (slope of (R)esponse vs. ln(C)oncentration graph).
1. Graph and find ------------
d ln C
mHg)
R vs Ln(C)
80
60
40
20
0
10 10 10
Dose (mg)
dR
------------ = 32.96
d ln C
dR
dt

R vs T
75
70
65
60
55
50
45
20 25 30 35 40 45 50
Time (hr)
dR
------- = – 0.91
dt
dR
-------
dt
3. Find the ln(C)oncentration vs. (T)ime slope : ------------- : Note that your slope m = – K .
dR
------------
d ln C
–1
K = 0.028hr
–-------------
0.91
= – ( 0.028 )
32.96
4. Calculate t 1 ⁄ 2 =  0.693
-------------  .
K 
t 1 ⁄ 2 =  -----------------------
0.693 -
– 1
= 24.75hr
0.028hr

3.5.3 ANSWERS: PROPRANOLOL

dR (slope of (R)esponse vs. ln(C)oncentration graph).
1. Graph and find ------------
d ln C
20
15
10
0
10 10
dR
------------ = 16.36
d ln C
dR
dt
25
20
15
10
5
0 1 2 3 4 5 6
dR
------- = – 2.93
dt

dR
-------
dt
3. Find the ln(C)oncentration vs. (T)ime slope : ------------- : Note that your slope m = – K .
dR
------------
d ln C
–1
K = 0.179hr
–-------------
2.93
= – 0.179
16.36
4. Calculate t 1 ⁄ 2 =  0.693
-------------  .
K 
t 1 ⁄ 2 =  -----------------------
0.693 -
– 1
= 3.87hr
0.179hr

CHAPTER 4 I.V. Bolus Dosing

OBJECTIVES
For an IV one compartment model plasma and urine:
1. Given patient drug and/or metabolite concentration, amount, and/or rate vs. time
profiles, the student will calculate (III) the relevant pharmacokinetic parameters
available from IV plasma, urine or other excreta data: e.g.
V d, K, k m, k r, AUC, AUMC, CL, MRT, t 1 ⁄ 2
2. The student will provide professional communication regarding the pharmacoki-
netic parameters obtained to patients and other health professionals.
3. The student will be able to utilize computer programs for simulations and data
analysis.

I.V. Bolus Dosing
4.1 I.V. Bolus dosing of Parent compound
4.1.1 PLASMA
Valid equations: ln C p = – K ⋅ t + ln C p 0 (EQ 4-1)
(Obtained from the
LaPlace transforms
ln X = – K ⋅ t + ln X0 (EQ 4-2)
derived from the
appropriate models
– Kt
derived from the C p = C p0 e (EQ 4-3)
pharmacokinetic
descriptions of the drug)
D-
C p 0 = ----- (EQ 4-4)
Vd
t ½ = 0.693
------------- (EQ 4-5)
K
( ∞)
( Cp n + Cp n + 1 ) Cp last
AUC = ∫ Cp dt = Σ  ------------------------------------- ⋅ ∆t + -------------- (EQ 4-6)
2 K
0
( ∞) t
( t n ⋅ Cp n ) + ( t n + 1 ⋅ Cp n + 1 ) Cp l ast ( t l ast ⋅ Cp last )
AUMC = ∫ t ⋅ C p dt = ∑  -------------------------------------------------------------------
2
- ⋅ ∆t + --------------- + ----------------------------------

K
2 K
(EQ 4-7)
0 0
MRT = AUMC
------------------ (EQ 4-8)
AUC
Cl = K ⋅ Vd (EQ 4-9)
Utilization:
Can you determine the • You should be able to plot a data set Concentration vs. time on semilog yielding a straight line
slope and intercept from with slope = – K and an intercept of C p0 .
a graph? Plot the data
in table 4 -1.on semi-log
graph paper. Extrapo-
late the line back to time TABLE 4-1 Nifedipine 25 mg IV bolus
= 0 to get Cp0. Find the
Cp
half life. Calculate the Time (hr) (mcg/L)
elimination rate con-
2 139
stant.
4 65.6
6 31.1
8 14.6
FIGURE 4-1.

I.V. Bolus Dosing
Does your Graph look FIGURE 4-1 Nifedipine IV Bolus (25 mg IV Bolus)
like this?
100 10 3
Concentration (mic/L)
Cp0 = 295 mic/L
-K1 = -0.375 hr -1
10 2
50 1.85 hr
10 1
0 2 4 6 8
Time (hr)
Time (hours)
• You should be able to determine K. A plot of the data in TABLE 4-1 results in FIGURE 4-1
dy
Remember from high school algebra, the slope of any straight line is the rise over the run, ------ ,
dx
In the case of semi-log graphs dy is the difference in the logarithms of the concentrations. Thus,
using the rules of logarithms, when two logs are subtracted, the numbers themselves are
divided. i.e. ln ( C1 ) – ln ( C2 ) = ln  ------- . Thus if we are judicious in the concentrations that we
C1
C2
take, we can set the rise to a constant number. So, if we take any two concentrations such that
one concentration is half of the other (In FIGURE 4-1 above, we took 100 and 50), the time it
takes for the concentration to halve is the half life (in the graph above, 1.85 hr). Then
0.693 0.693 –1
K = ------------- = ---------------- = 0.375 hr
t½ 1.85hr
• You should be able to determine V d :. To do this, extrapolate the line to t = 0 . The value of Cp
mic
when t = 0 is C p0 (in the graph above, C p0 = 295 --------- which is equal to D ⁄ V d for an IV bolus
L
dose only.
Dose 25mg ⋅ 1000mic
Thus, Cp 0 = ------------- , V d = Dose
------------- = ------------------ --------------------- = 85L
Vd Cp 0 295mic mg
------------------
L
The volume of distribution is a mathematical construct. It is merely the proportionality constant
between two knowns - the C p0 which results from a given D 0 . It is, however, useful because it
is patient specific and therefore can be used to predict how the patient will treat a subsequent
dose of the same drug. You should be able to obtain the volume of distribution from graphical
analysis of the data. Pay attention to the units! Make sure that they are consistent on both sides
of the equation. NOTE: the volume of distribution is not necessarily any physiological space.
For example the approximate volume of distribution of digoxin is about 600 L If that were a
physiological space and I were all water, that would mean that I would weigh about 1320
pounds. I’m a little overweight (I prefer to think that I’m underheight), but REALLY!
• Given any three of the variables of the IV bolus equation, either by direct information (the vol-
ume of distribution is such and such) or by graphical data analysis, you should be able to find
the fourth.

I.V. Bolus Dosing
• You should be able to calculate Area Under the Curve (AUC) from IV Bolus data (Time vs. Cp).
From the above data in TABLE 4-1 the AUC is calculated using (EQ 4-6):
(∞)
Cpn + Cp n + 1 Cp
AUC = ∫ Cp dt = Σ  --------------------------------- + --------l which in this case is:
 ∆t  K
0
 Cp o + Cp 1 Cp 1 + Cp 2 Cp2 + Cp 3 Cp 3 + Cp last Cp l ast 

Σ  -------------------------- ⋅ ∆t 1 + -------------------------- ⋅ ∆t 2 + -------------------------- ⋅ ∆t 3 + ------------------------------- ⋅ ∆t last + --------------
-
 2 2 2 2 K1 
 295 + 139 139 + 65.6 65.6 + 31.1 31.1 + 14.6 14.6 mcg
Σ  ------------------------ ⋅ 2 + ------------------------- ⋅ 2 + --------------------------- ⋅ 2 + --------------------------- ⋅ 2 + ------------- ---------- hr or
 2 2 2 2 0.375  L
mcg mcg
Σ { 434 + 204.6 + 96.7 + 45.7 + 38.9 } ---------- hr = 819.9 ---------- hr . In tabular format, the AUC calculation
L L
is shown in TABLE 4-2.
TABLE 4-2 AUC
t t
AUC AUC
TIME Cp t–1 0
0 295
2 139 434.0 434.0
4 65.6 204.6 638.6
6 31.1 96.7 735.3
8 14.6 45.7 781.0
∞ 0 38.9 819.9
The AUC of a plot of plasma concentration vs. time, in linear pharmacokinetics, is a number
which is proportional to the dose of the drug which gets into systemic circulation. The propor-
tionality constant, as before, is the volume of distribution. It is useful as a tool to compare the
amount of drug obtained by the body from different routes of administration or from the same
route of administration by dosage forms made by different manufacturers (calculate bioavail-
ability in subsequent discussions).
The AUC of a plot of Rate of Excretion of a drug vs. time, in linear pharmacokinetics, is the
mass of drug excreted into the urine, directly.
• You should be able to calculate the AUMC from IV Bolus data (Time vs. Cp). The equation for
AUMC is equation 4-7:
( ∞) t
( t n ⋅ Cp n ) + ( t n + 1 ⋅ Cp n + 1 ) Cp l ast ( t l ast ⋅ Cp last )
AUMC = ∫ t ⋅ C p dt = ∑  -------------------------------------------------------------------
2
- ⋅ ∆t + --------------- + ----------------------------------

K
2 K
which in the
0 0
data given in TABLE 4-1 is:
T0 ⋅ C po + T1 ⋅ C p1 T1 ⋅ C p1 + T2 ⋅ C p2 T 2 ⋅ C p 2 + T3 ⋅ C p3
Σ ----------------------------------------------- ⋅ ∆t 1 + ----------------------------------------------- ⋅ ∆t 2 + ----------------------------------------------- ⋅ ∆t 3 +
2 2 2

I.V. Bolus Dosing
T 3 ⋅ C p 3 + T last ⋅ C p last T last ⋅ C p l ast Cplast

---------------------------------------------------------- ⋅ ∆t l ast + ------------------------------
- + --------------- and thus,
2 K K
2
 0 ⋅ 295 + 2 ⋅ 139 2 ⋅ 139 + 4 ⋅ 65.6 4 ⋅ 65.6 + 6 ⋅ 31.1 mcg 2

Σ  --------------------------------------- ⋅ 2 + ---------------------------------------- ⋅ 2 + ------------------------------------------ ⋅ 2 ---------- hr +
 2 2 2  L
 6 ⋅ 31.1 + 8 ⋅ 14.6 ⋅ 14.6 14.6  mcg 2

- ⋅ 2 + 8-----------------
 ----------------------------------------- - + ----------------  ---------- hr or
 2 0.375 0.375  L
2
mcg 2
Σ { 278 + 540.4 + 449 + 303.4 + 311.47 + 103.82 } = 1986.1 ---------- hr
L
Thus in tabular format the AUMC for data given in TABLE 4-1 is TABLE 4-3 below.
TABLE 4-3 AUMC
t
AUMC t AUMC
TIME Cp Cp*T 0
0 295 0
2 139 278 278.0 278.0
4 65.6 262.4 540.4 818.4
6 31.1 186.6 449.0 1267.4
8 14.6 116.8 303.4 1570.8
∞ 0 0 415.3 1986.1
The AUMC is the Area Under the first Moment Curve. A plot of T*Cp vs. T is the first
moment curve. The time function buried in this plot, the Mean Residence Time (MRT), can be
extracted using equation 4-8 below.
It is the geometric mean time that the molecules of drug stay in the body. It has utility in the fact
that, as drug moves from the dosage form into solution in the gut, from solution in the gut into
the body, and from the body out, each process is cumulatively additive. That means if we can
physically separate each of these processes in turn, we can calculate the MRT of each process.
The MRT of each process is the the inverse of the rate constant for that process.
• You should be able to calculate MRT from IV Bolus data (Time vs. Cp) using equation 4-8
AUMC 1986.1
MRT = ------------------ = ---------------- = 2.42
AUC 819.9
Since there is only the process of elimination (no release of the drug from the dosage form, no
absorption), the MRT is the inverse of the elimination rate constant, K. Thus MRT = 1/K.

I.V. Bolus Dosing
Flow Chart 4-1 IV Bolus
K
X
MRT(IV) = 1/K
Suppose the drug were given in a solution. Then the drug would have to be absorbed and then
eliminated. Since the MRTs are additive, the MRT of the oral solution would be made up of the
MRTs of the two processes, thus:
Flow Chart 4-2 Oral Solution
Ka K
Xa X
MRT(os) = MAT(os)+MRT(IV)
MRT(os) = 1/Ka + 1/K
Consequently, if a drug has to be released from a dosage form for the drug to get into solution
which is subsequently absorbed, a tablet for example, the MRT of the tablet will consist of the
MRT(IV) and the MAT(os) and the Mean Dissolution Time (MDT), thus:
Flow Chart 4-3 Tablet
Kd Ka K
Xd Xa X
MRT(tab) = MDT + MAT(os) + MRT(IV)

MRT(tab) = 1/Kd + 1/Ka + 1/K
MRT(tab) = MAT(tab) + MRT(IV)
MRT(tab) = 1/Ka (apparent) + 1/K

I.V. Bolus Dosing
Normally, we don’t have information from the oral solution, just IV and tablet. So in that case
the information obtained about absorption from the tablet is bundled together into an apparent
absorption rate constant consisting of both dissolution and absorption.
It should be apparent that this is a reasonably easily utilized and powerful tool used to obtain
pharmacokinetic parameters.

I.V. Bolus Dosing
4.1.2 IV BOLUS, PARENT COMPOUND, PLASMA PROBLEMS

Equations used in this 1. K = –slope from equation 4-3
section:
ln 2- equation 4-5
2. t 1 ⁄ 2 = -------
K
1
3. MRT = ---- ( estimate ) MRT = AUMC
------------------ equation 4-8
K AUC
4. Cp 0 = the y-intercept of the line from equation 4-3
Cp ∞
5. Estimate for AUC = AUC = ---------0 which is
K ∫0 Cp dt
(∞)
( Cp n + Cp n + 1 ) Cp last
AUC = ∫ Cp dt = Σ  ------------------------------------- ( ∆t ) + --------------
2  K
0
Trapezoidal rule applied to equation 4-6
6. Estimate for AUMC = AUMC = AUC ⋅ MRT from equation 4-8
( ∞) t
( t n ⋅ Cp n ) + ( t n + 1 ⋅ Cp n + 1 ) Cp last ( t last ⋅ Cp l ast )
AUMC ∫ Cp dt = ∑  -------------------------------------------------------------------
2
- ⋅ ∆t n + --------------- + ----------------------------------

K
2 K
0 0
from equation 4-7
7. V d = Dose
------------- from equation 4-4
Cp 0
Cp 0 Dose
8. Cl = K1 ⋅ V d = ------------ ⋅ ------------- = Dose
-------------
AUC Cp 0 AUC

I.V. Bolus Dosing
Acyclovir (Problem 4 - 1)
Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
De Miranda and Burnette, “Metabolic Fate and Pharmacokinetics of the Acyclovir Prodrug Valaciclovir in Cynomolgus Mon-
keys”, Drug Metabolism and Disposition (1994): 55-59.
Acyclovir is an antiviral drug used in the treatment of herpes simplex, varicella zoster, and in suppressive therapy. In
this study, three male cynomolgus monkeys were each given a 10 mg ⁄ kg intravenous dose. The monkeys weighed an
average of 3.35 kg each. Blood samples were collected and the following data was obtained:
PROBLEM TABLE 4 - 1. Acyclovir
Serum concentration
Time (hours) ( µg ⁄ mL )
0.167 26.0
0.300 23.0
0.500 19.0
0.75 16.0
1.0 12.0
1.5 7.0
2.0 5.0
From the data presented in the Preceding table, determine the following:
1. Find the elimination rate constant, k .
2. Find the half life, t ½ .
3. Find MRT .
4. Find ( C p )0 .
5. Find the Area Under the Curve, AUC .
6. Find the area under the first moment curve, AUMC .
7. Find the volume of distribution, V d
8. Find the clearance, Cl .

I.V. Bolus Dosing
(Problem 4 - 1) Acyclovir:
2
10
CONCENTRATION (MIC/ML)
1
10
100
0.0 0.5 1.0 1.5 2.0
TIME (HR)
–1
1. k = 0.93hr
2. t½ = 0.75hr .
3. MRT = 1.08hr .
4. ( C p )0 = 30.4ug ⁄ mL .
5. AUC = 32.75ug ⁄ mL ⋅ hr .
2
6. AUMC = 35.2ug ⁄ mL ⋅ hr .
7. Vd = 1.1L
8. Cl = 1.02L ⁄ hr .

I.V. Bolus Dosing
Aluminum (Problem 4 - 2)
Xu, Pai, and Melethil, "Kinetics of Aluminum in Rats. II: Dose-Dependent Urinary and Biliary Excretion", Journal of Pharmaceu-
tical Sciences, Oct 1991, p 946 - 951.
A study by Xu, Pai, and Melethil establishes the pharmacokinetics of Aluminum in Rats. In this study, four rats with an
average weight of 375g, were given an IV bolus dose of aluminum (1 mg/kg). Blood samples were taken at various
intervals and the following data was obtained:
PROBLEM TABLE 4 - 2. Aluminum
ng
Serum concentration, --------
Time (hours) mL
0.4 19000
0.6 18000
1.4 15000
1.6 14500
2.3 12500
3.0 10500
4.0 8500
5.0 6500
6.0 5000
8.0 3250
10.0 2000
12.0 1250
From the data presented in the preceding table, determine the following:
3. Find MRT .
4. Find ( C p )0 .

I.V. Bolus Dosing
(Problem 4 - 2) Aluminum:
5
10
CONCENTRATION (NG/ML)
4
10
3
10
0 2 4 6 8 10 12
TIME (HR)
–1
1. k = 0.234hr
2. t½ = 3hr .
3. MRT = 4.3hr .
4. ( C p )0 = 21000ng ⁄ mL .
5. AUC = 89285ng ⁄ mL ⋅ hr .
2
6. AUMC = 383926ng ⁄ mL ⋅ hr .
7. Vd = 17.86mL
8. Cl = 4.18mL ⁄ hr .

I.V. Bolus Dosing
Amgen (Problem 4 - 3)
Salmonson, Danielson, and Wikstrom, "The pharmacokinetics of recombinant human erythropoetin after intravenous and subcuta-
neous administration to healthy subjects", Br. F. clin. Pharmac. (1990), p 709- 713.
Amgen (r-Epo) is a form of recombinant erythropoetin. Erythropoetin is a hormone that is produced in the kidneys and
used in the production of red blood cells. The kidneys of patients who have end-stage renal failure cannot produce
erythropoetin; therefore, r-Epo is being investigated for use in these patients in order to treat the anemia that results
from the lack of erythropoetin. In a study by Salmonson et al, six healthy volunteers were used to demonstrate that
both IV and subcutaneous administration of erythropoetin have similar effects in the treatment of anemia due to
chronic renal failure. The six volunteers were each given a 50 U/kg intravenous dose of Amgen. The average weight
of the six volunteers was 79 kg. Blood samples were drawn at various times and the data obtained is summarized
below:
PROBLEM TABLE 4 - 3. Amgen
mU
Serum concentration, ---------
Time (hours) mL
2 700
4 600
6 400
8 300
12 150
24 40
3. Find MRT .
4. Find ( C p )0 .

I.V. Bolus Dosing
(Problem 4 - 3) Amgen:
103
CONCENTRATION (MU/ML)
102
Con (mU/mL)
101
0 5 10 15 20 25
TIME (HR)
–1
1. k = 0.134hr
2. t½ = 5.2hr .
3. MRT = 7.46hr .
4. ( C p )0 = 900mU ⁄ mL .
5. AUC = 6945mU ⁄ mL ⋅ hr .
2
6. AUMC = 49600 mU ⁄ mL ⋅ hr .
7. Vd = 4.44L
8. Cl = 0.6L ⁄ hr .

I.V. Bolus Dosing
Atrial Naturetic Peptide (ANP) (Problem 4 - 4)

Brier and Harding, "Pharmacokinetics and Pharmacodynamics of Atrial Naturetic Peptide after Bolus and Infusion Administra-
tion in the Isolated Perfused Rat Kidney", The Journal of Pharmacology and Experimental Therapeutics (1989), p 372 - 377.
A study by Brier and Harding a dose of 45 ng was given by IV bolus to rats. Samples of blood were taken at various
intervals throughout the length of the study and the following data was obtained:
PROBLEM TABLE 4 - 4. Atrial Naturetic Peptide (ANP)
pg
Time (minutes) mL
3 380
10 280
20 170
30 130
40 100
50 70
60 50
3. Find MRT .
4. Find ( C p )0 .

I.V. Bolus Dosing
(Problem 4 - 4) Atrial Naturetic Peptide (ANP):
103
Con CONCENTRATION (PG/ML)
102
(pg/mL)
101
0 10 20 30 40 50 60
Time (min)
–1
1. k = 0.0345min
2. t½ = 20.09min .
3. MRT = 28.95min .
4. ( C p )0 = 386.6pg ⁄ mL .
5. AUC = 11206.4pg ⁄ mL ⋅ min .

2
6. AUMC = 324425.4pg ⁄ mL ⋅ min .
7. Vd = 116.4mL
8. Cl = 4.02mL ⁄ min .

I.V. Bolus Dosing
Aztreonam (Problem 4 - 5)
Cuzzolim et al., "Pharmacokinetics and Renal Tolerance of Aztreonam in Premature Infants", Antimicrobial Agents and Chemo-
therapy (Sept. 1991), p. 1726 - 1928.
Aztreonam is a monolactam structure which is active against aerobic, gram-negative bacilli. The pharmacokinetic
parameters of Aztreonam were established in a study presented in by Cuzzolim et al in which Aztreonam (100 mg/ kg)
was administered intravenously to 30 premature infants over 3 minutes every 12 hours. The group of neonates had an
average weight of 1639.6g. The following set of data was obtained:
PROBLEM TABLE 4 - 5. Aztreonam
µg
Time (minutes) mL
1 40.50
2 34.99
3 29.99
4 23.88
5 22.20
6 19.44
7 16.55
8 14.99
3. Find MRT .
4. Find ( C p )0 .

I.V. Bolus Dosing
(Problem 4 - 5) Aztreonam:
10 2
CONCENTRATION (UG/ML)
Con (ug/mL)
10 1
0 2 4 6 8
TIME (MIN)
–1
1. k = 0.144min
2. t½ = 4.81min .
3. MRT = 6.94min .
4. ( C p )0 = 45.75ug ⁄ mL .
5. AUC = 317.7ug ⁄ mL ⋅ min .

2
6. AUMC = 2204.8ug ⁄ mL ⋅ min .
7. Vd = 3.58L
8. Cl = 0.516L ⁄ min .

I.V. Bolus Dosing
Recombinant Bovine Placental Lactogen (Problem 4 - 6)

Byatt, et. al., "Serum half-life and in-vivo actions of recombinant bovine placental lactogen in the dairy cow", Journal of Endocri-
nology (1992), p. 185 - 193.
Bovine placental lactogen (bPL) is a hormone similar to growth hormone and prolactin. It binds to both prolactin and
growth hormone receptors in the rabbit and stimulates lactogenesis in the rabbit. In a study by Byatt, et. al., four cows
(2 pregnant and 2 nonpregnant) were given IV bolus injections of 4 mg and the following data was obtained:
PROBLEM TABLE 4 - 6. Recombinant Bovine Placental Lactogen
µg
Serum concentration ------
Time (minutes) L
3.8 117
6.8 72
12.0 43
16.0 27
20.0 18
3. Find MRT .
4. Find ( C p )0 .

I.V. Bolus Dosing
(Problem 4 - 6) Recombinant Bovine Placental Lactogen:

103
(MIC/L)
ConCONCENTRATION
102
(ug/L)
101
0 5 10 15 20
Time (min)
–1
1. k = 0.113min
2. t½ = 6.13min .
3. MRT = 8.85min .
4. ( C p )0 = 167.8ug ⁄ L .
5. AUC = 1484.9ug ⁄ L ⋅ min .

2
6. AUMC = 13141.1ug ⁄ L ⋅ min .
7. Vd = 23.84L
8. Cl = 2.69L ⁄ min .

I.V. Bolus Dosing
Caffeine (Problem 4 - 7)
Dorrbecker et. al., "Caffeine and Paraxanthine Pharmacokinetics in the Rabbit: Concentration and Product Inhibition Effects.",
Journal of Pharmacokinetics and Biopharmaceutics (1987), p.117 - 131.
This study examines the pharmacokinetics of caffeine in the rabbit. In this study type I New Zealand White rabbits
were given an 8 mg intravenous dose of caffeine. Blood samples were taken and the following data was obtained:
PROBLEM TABLE 4 - 7. Caffeine
µg
Serum concentration --------
Time (minutes) mL
12 3.75
40 2.80
65 2.12
90 1.55
125 1.23
173 0.72
243 0.37
3. Find MRT .
4. Find ( C p )0 .

I.V. Bolus Dosing
(Problem 4 - 7) Caffeine:
Caffeine
101
100
10-1
Con (ug/L)
0 50 100 150 200 250
Time (min)
–1
1. k = 0.00997min
2. t½ = 69.51min .
3. MRT = 100.3min .
4. ( C p )0 = 4.105ug ⁄ mL .
5. AUC = 411.7ug ⁄ mL ⋅ min .

2
6. AUMC = 41293.5ug ⁄ mL ⋅ min .
7. Vd = 1.95L
8. Cl = 19.44mL ⁄ min .

I.V. Bolus Dosing
Ceftazidime (Problem 4 - 8)
Demotes-Mainard, et. al., "Pharmacokinetics of Intravenous and Intraperitoneal Ceftazidime in Chronic Ambulatory Peritoneal
Dyialysis", Journal of Clinical Pharmacology (1993), p. 475 - 479.
Ceftazidime is a third generation cephalosporin which is administered parenterally. In this study, eight patients with
chronic renal failure were each given 1 g of ceftazidime intravenously. Both blood samples were taken the data
obtained from the study is summarized in the following table:
PROBLEM TABLE 4 - 8. Ceftazidime
mg
Serum concentration -------
Time (hours) L
1 50
2 45
4 38
24 21
36 14
48 11
60 8
72 4
3. Find MRT .
4. Find ( C p )0 .

I.V. Bolus Dosing
(Problem 4 - 8) Ceftazidime:
102
CONCENTRATION (MG/L)
101
Con (mg/L)
100
0 20 40 60 80
Time (hours)
–1
1. k = 0.0324hr
2. t½ = 21.39hr .
3. MRT = 30.86hr .
4. ( C p )0 = 47.57mg ⁄ L .
5. AUC = 1468.2mg ⁄ L ⋅ hr .
2
6. AUMC = 45308.6mg ⁄ L ⋅ hr .
7. Vd = 21.02L
8. Cl = 0.681L ⁄ hr .

I.V. Bolus Dosing
Ciprofloxacin (Problem 4 - 9)
Lettieri, et. al., "Pharmacokinetic Profiles of Ciprofloxacin after Single Intravenous and Oral Doses", Antimicrobial Agents and
Chemotherapy (May 1992), p. 993 -996.
Ciprofloxacin is a fluoroquinolone antibiotic which is used in the treatment of infections of the urinary tract, lower res-
piratory tract, skin, bone, and joint. In this study, twelve healthy, male volunteers were each given 300 mg intravenous
doses of Ciprofloxacin. Blood and urine samples were collected at various times throughout the day and the following
data was collected:
PROBLEM TABLE 4 - 9. Ciprofloxacin
mg
Time (hours) L
2 1.20
3 0.85
4 0.70
6 0.50
8 0.35
10 0.25
3. Find MRT .
4. Find ( C p )0 .

I.V. Bolus Dosing
(Problem 4 - 9) Ciprofloxacin:
101
100
Con (mg/L)
10-1
0 2 4 6 8 10
Time (hours)
–1
1. k = 0.1875hr
2. t½ = 3.7hr .
3. MRT = 5.33hr .
4. ( C p )0 = 1.57mg ⁄ L .
5. AUC = 8.395mg ⁄ L ⋅ hr .
2
6. AUMC = 44.74mg ⁄ L ⋅ hr .
7. Vd = 190.6L
8. Cl = 35.74L ⁄ hr .

I.V. Bolus Dosing
The effect of Probenecid on Diprophylline (DPP) (Problem 4 - 10)

Nadai et al, "Pharmacokinetics and the Effect of Probenecid on the Renal Excretion Mechanism of Diprophylline", Journal of
Pharmaceutical Sciences (Oct 1992), p. 1024 - 1027.
Diprophylline is used as a bronchodilator. A study by Nadai et al was designed to determine whether or not coadmin-
istration of Diprophylline with Probenecid affected the pharmacokinetic parameters of Diprophylline. In this study,
male rats (average weight: 300 g) were given 60 mg/kg of Diprophylline intravenously and a 3 mg/kg loading dose of
Probenecid followed by a continuous infusion of 0.217 mg/min/kg of Probenecid. The following set of data was
obtained for Diprophylline (DPP):
PROBLEM TABLE 4 - 10. The effect of Probenecid on Diprophylline (DPP)
µg
Time (minutes) mL
16 40.00
31 27.00
60 13.00
91 6.50
122 3.50
3. Find MRT .
4. Find ( C p )0 .

I.V. Bolus Dosing
(Problem 4 - 10) The effect of probenecid on diprophylline (DPP):
102
101
Con (ug/mL)
100
0 20 40 60 80 100
Time (min)
–1
1. k = 0.023min
2. t½ = 30.13min .
3. MRT = 43.48min .
4. ( C p )0 = 55.13ug ⁄ mL .
5. AUC = 2396.96ug ⁄ mL ⋅ min .

2
6. AUMC = 104219.8ug ⁄ mL ⋅ min .
7. Vd = 326.5mL
8. Cl = 7.5mL ⁄ min .

I.V. Bolus Dosing
Epoetin (Problem 4 - 11)

MacDougall et. al., "Clinical Pharmacokinetics of Epoetin (Recombinant Human Erythropoetin", Clinical Pharmacokinetics
(1991), p 99 - 110.
Epoetin is recombinant human erythropoetin. Erythropoetin is a hormone that is produced in the kidneys and used in
the production of red blood cells. The kidneys of patients who have end-stage renal failure cannot produce erythropo-
etin; therefore, Epoetin is used in these patients to treat the anemia that results from the lack of erythropoetin. Epoetin
has also been used in the treatment of anemias resulting from AIDS. malignant disease, prematurity, rheumatoid arthri-
tis, sickle-cell anemia, and myelosplastic syndrome. In a study by Macdougall et al, eight patients who were on perito-
neal dialysis (CAPD) were given an IV bolus dose of 120 U/kg which decayed monoexponentially from a peak of 3959
U/L to 558 U/L at 24 hours. The following data was obtained:
PROBLEM TABLE 4 - 11. Epoetin
U
Serum concentration ----
Time (hours) L
0.0 4000
0.5 3800
1.0 3600
2.0 3300
3.0 3000
4.0 2550
5.0 2350
6.0 2150
7.0 1900
From the data presented in the preceding table and assuming that the patient weighs 65 kg, determine the following:
3. Find MRT .
4. Find ( C p )0 .

I.V. Bolus Dosing
(Problem 4 - 11) Epoetin:
104
CONCENTRATION (U/L)
Con (U/L)
103
0 1 2 3 4 5 6 7
Time (hours)
–1
1. k = 0.107 hr
2. t½ = 6.5 hr .
3. MRT = 9.38 hr .
4. ( C p )0 = 4023 Units/L .
Units ⋅ hr
5. AUC = 37775 ------------------------ .
L
2
Units ⋅ hr
6. AUMC = 354697 --------------------------- .
L
7. Vd = 1.9 L
L
8. Cl = 0.2065 ----- .
hr

I.V. Bolus Dosing
Famotidine (Problem 4 - 12)

Kraus, et. al., "Famotidine--Pharmacokinetic Properties and Suppression of Acid Secretion in Pediatric Patients Following Car-
diac Surgery", Clinical Pharmacokinetics (1990), p 77 - 80.
Famotidine is a histamine H2-receptor antagonist. The study by Kraus, et. al., focuses on the kinetics of famotidine in
children. In the study, ten children with normal kidney function and a body weight ranging from 14 - 25 kg, were each
given a single intravenous 0.3 mg/kg dose of famotidine. Blood and urine samples were taken providing the following
data:
PROBLEM TABLE 4 - 12. Famotidine
µg
Serum concentration ------
Time (hours) L
0.33 300
0.50 250
1.00 225
4.00 125
8.00 70
12.00 40
16.00 15
From the data presented in the preceding table, determine the following assuming that the patient weighs 17.2 kg:
3. Find MRT .
4. Find ( C p )0 .

I.V. Bolus Dosing
(Problem 4 - 12) Famotidine:
10 3
(MIC/L)
ConCONCENTRATION
10 2
(ug/mL)
10 1
0 5 10 15 20
Time (hours)
–1
1. k = 0.17 hr
2. t½ = 3.9 hr .
3. MRT = 5.7 hr .
µg
4. ( C p )0 = 285 ------ .
L
µg ⋅ hr
5. AUC = 1600 ----------------- .
L
2
µg ⋅ hr
6. AUMC = 9000 ------------------ .
L
7. Vd = 18 L
8. Cl = 3.2L .

I.V. Bolus Dosing
Ganciclovir (Problem 4 - 13)

Trang, et. al., "Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections", Clin-
ical Pharmacology and Therapeutics (1993), p. 15 - 21.
Ganciclovir (mw: 255.23) is used against the human herpes viruses, cytomegalovirus retinitis, and cytomegalovirus
infections of the gastrointestinal tract. In this study, twenty-seven newborns with cytomegalovirus disease were given
4 mg/kg of ganciclovir intravenously over one hour. Blood samples were taken and the data obtained is summarized in
the following table:
PROBLEM TABLE 4 - 13. Ganciclovir
Time (hours) Serum concentration

1.50 4.50
2.00 4.00
3.00 3.06
4.00 2.40
6.00 1.45
8.00 0.87
From the data presented in the preceding table and assuming the patient weighs 3.6 kg, determine the following :
3. Find MRT .
4. Find ( C p )0 .

I.V. Bolus Dosing
(Problem 4 - 13) Ganciclovir:
10
CONCENTRATION (MICMOLE/L)
10
10
0 2 4 6 8
TIME (HR)
–1
1. k = 0.288hr
2. t½ = 2.4hr .
3. MRT = 3.5hr .
µmole
4. ( C p )0 = 23 ---------------- .
mL
µmole ⋅ hr
5. AUC = 80 -------------------------- .
mL
2
µmole ⋅ hr
6. AUMC = 280 ----------------------------- .
mL
mg 1000µg
4 ------- ⋅ 3.6kg ⋅ -------------------
Dose kg mg
7. Vd = ------------- = ------------------------------------------------------------- = 2.45L
Cp 0 µmole µg
23 ---------------- ⋅ 255.23 ----------------
L µmole
L
8. Cl = 0.7 ----- .
hr

I.V. Bolus Dosing
Imipenem (Problem 4 - 14)

Heikkila, Renkonen, and Erkkola, "Pharmacokinetics and Transplacental Passage of Imipenem During Pregnancy", Antimicrobial
Agents and Chemotherapy (Dec. 1992), p 2652 - 2655.
Imipenem is a beta-lactam antibiotic which is used in combination with cilastin and is active against a broad spectrum
of bacteria. The pharmacokinetics of Imipenem in pregnant women is established in this study. Twenty women (six of
which were non-pregnant controls) were given a single intravenous dose of 500 mg of imipenem-cilastin (1:1). Blood
samples were taken at various intervals and the data obtained is summarized in the following table:
PROBLEM TABLE 4 - 14. Imipenem
mg
Time (minutes) L
10 27.00
15 23.50
30 15.50
45 9.50
60 6.50
3. Find MRT .
4. Find ( C p )0 .

I.V. Bolus Dosing
(Problem 4 - 14) Imipenem:

2
10
1
10
0
10
0 10 20 30 40 50 60
TIME (MIN)
–1
1. k = 0.029 min
2. t½ = 24 min .
3. MRT = 34.5 min .

mg
4. ( C p )0 = 36.2 ------- .
L
mg ⋅ min
5. AUC = 1250 --------------------- .
L
2
mg ⋅ min
6. AUMC = 43125 ------------------------ .
L
Dose 500mg
7. Vd = ------------- = ------------------ = 13.8L
Cp 0 mg
36.2 -------
L
L
8. Cl = 0.4 --------- .
min

I.V. Bolus Dosing
Methylprednisolone (Problem 4 - 15)

Patel, et. al., "Pharmacokinetics of High Dose Methylprednisolone and Use in Hematological Malignancies", Hematological
Oncology (1993), p. 89 - 96.
Methylprednisolone is a corticosteriod that has been used in combination chemotherapy for the treatment of hemato-
logical malignancy, myeloma, and acute lymphoblastic leukemia. In a study by Patel et. al., eight patients were given
1.5 gram intravenous doses of methylprednisolone from which the following data was obtained:
PROBLEM TABLE 4 - 15. Methylprednisolone
µg
Time (hours) mL
0.5 19.29
1.0 17.56
1.8 15.10
4.0 9.98
5.8 7.10
8.0 4.70
12.0 2.21
18.0 0.71
24.0 0.23
3. Find MRT .
4. Find ( C p )0 .

I.V. Bolus Dosing
(Problem 4 - 15) Methylprednisolone:
102
101
100
Con (ug/mL)
10-1
0 5 10 15 20 25
Time (hours)
–1
1. k = 0.188 hr
2. t½ = 3.69hr .
3. MRT = 5.3hr .
µg
4. ( C p )0 = 21.2 -------- .
mL
µg ⋅ hr
5. AUC = 112.5 ----------------- .
mL
2
µg ⋅ hr
6. AUMC = 598.4 ------------------ .
mL
7. Vd = 71L
L
8. Cl = 13.3 ----- .
hr

I.V. Bolus Dosing
Omeprazole (Problem 4 - 16)

Anderson, et. al., "Pharmacokinetics of [14C] Omeprazole in Patients with Liver Cirrhosis", Clinical Pharmacokinetics (1993), p.
71 - 78.
Omeprazole (mw: 345.42) is a gastric proton-pump inhibitor which decreases gastric acid secretion. It is effective in
the treatment of ulcers and esophageal reflux. In normal patients 80% of the omeprazole dose is excreted as metabo-
lites in the urine and the remainder is excreted in the feces. In the study by Anderson, et. al., eight patients with liver
cirrhosis were given 20 mg, IV bolus doses of omeprazole. The patients had a mean body weight of 70 kg. Both blood
were taken at various intervals throughout the study and the following data was obtained:
PROBLEM TABLE 4 - 16. Omeprazole
ρmole
Serum concentration ----------------
Time (hours) mL
0.75 3.49
1.00 3.25
2.00 2.46
3.00 1.86
4.00 1.40
5.00 1.06
6.00 0.80
7.00 0.61
8.00 0.46
10.00 0.26
12.00 0.15
From the data presented in the preceding table, determine the following :
3. Find MRT .
4. Find ( C p )0 .

I.V. Bolus Dosing
(Problem 4 - 16) Omeprazole:
10 1
(umol/mL) (PICOMOLE/ML)
10 0
ConCONCENTRATION
10-1
0 2 4 6 8 10 12
Time (hours)
–1
1. k = 0.280hr
2. t½ = 2.5hr .
3. MRT = 3.57hr .
ρmole
4. ( C p )0 = 4.3 ---------------- .
mL
ρmole ⋅ hr
5. AUC = 15.4 -------------------------- .
mL
2
ρmole ⋅ hr
6. AUMC = 55 ----------------------------- .
mL
Dose 20mg
7. Vd = ------------- = ------------------------------------------------------------------------------------------------------------ = 13465L
Cp 0 ρmole mmole
4.3 ---------------- ⋅ ------------------------ - ⋅ 345.42mg
------------------------ ⋅ 1000mL
--------------------
mL 10 ρmole mmole 9 L
L
8. Cl = 3.9 ----- .
hr

I.V. Bolus Dosing
Pentachlorophenol (Problem 4 - 17)

Reigner, Rigod, and Tozer, "Absorption, Bioavailability, and Serum Protein Binding of Pentachlorophenol in the B6C3F1 Mouse",
Pharmaceutical Research (1992), p 1053 - 1057.
Pentachlorophenol (PCP) is a general biocide. That is, it is an insecticide, fungicide, bactericide, herbicide, algaecide,
and molluskicide, that is used as a wood preservative. Extensive exposure to PCP can be fatal. In a study by Reigner
et al, six mice (average weight: 27 g) were given 15 mg/kg of PCP by intravenous bolus. Blood samples were taken at
various intervals from which the following data was obtained:
PROBLEM TABLE 4 - 17. Pentachlorophenol
µg
Time (hours) mL
0.083 38.00
4.000 22.00
8.000 14.00
12.000 7.90
24.000 1.30
28.000 0.75
32.000 0.60
36.000 0.40
From the data presented in the preceding table, determine the following :
3. Find MRT .
4. Find ( C p )0 .

I.V. Bolus Dosing
(Problem 4 - 17) Pentachlorphenol:
102
101
100
Con (ug/mL)
10-1
0 10 20 30 40
Time (hours)
–1
1. k = 0.134 hr
2. t½ = 5.2hr .
3. MRT = 7.5hr .
µg
4. ( C p )0 = 35.6 -------- .
mL
µg ⋅ hr
5. AUC = 281 ----------------- .
mL
2
µg ⋅ hr
6. AUMC = 2100 ------------------- .
mL
7. Vd = 11.4mL
ml
8. Cl = 1.5 ------ .
hr

I.V. Bolus Dosing
9-(2-phophonylmethoxyethyl) adenine (Problem 4 - 18)

Naesens, Balzarini, and Clercq, "Pharmacokinetics in Mice of the Anti-Retrovirus Agent 9-(2-phophonylmethoxyethyl) adenine",
Drug Metabolism and Disposition (1992), p. 747- 752.
9-(2-phophonylmethoxyethyl) adenine (PEMA) is an anti-retrovirus (anti-HIV) agent. The pharmacokinetics of

PEMA in mice were established in a study by . In this study there were three different PEMA doses given: 25 mg/kg,
100 mg/kg, and 500 mg/kg. Each of these doses was injected intravenously into male mice. The data obtained from
study using the 25 mg/kg dose is summarized in the following table:
PROBLEM TABLE 4 - 18. 9-(2-phophonylmethoxyethyl) adenine
µg
Time (minutes) mL
2.0 90.3
2.9 83.9
5.6 67.3
8.9 51.5
10.5 45.2
13.5 35.4
15.0 31.3
20.0 20.9
24.0 15.1
59.6 0.9
From the data presented in the preceding table, determine the following. (Assume that the mouse weighs 200g.)
3. Find MRT .
4. Find ( C p )0 .

I.V. Bolus Dosing
(Problem 4 - 18) Pema:
10 2
ConCONCENTRATION (MIC/ML) 10 1
10 0
(ug/mL)
10 -1
0 10 20 30 40 50 60
Time (min)
–1
1. k = 0.08min
2. t½ = 8.67min .
3. MRT = 12.5min .
µg
4. ( C p )0 = 105 -------- .
mL
µg ⋅ hr
5. AUC = 1300 ----------------- .
mL
2
µg ⋅ hr
6. AUMC = 16250 ------------------- .
mL
7. Vd = 47.6ml
mL
8. Cl = 3.8 --------- .
min

I.V. Bolus Dosing
Thioperamide (Problem 4 - 19)

Sakurai, et. al., "The Disposition of Thioperamide, a Histamine H3-Antagonist, in Rats", J. Pharm. Pharmacol. (1994), p. 209 -
212.
Thioperamide is a histamine (H3) receptor-antagonist. In a study by Sakurai et al, rats were given 10 mg/kg intrave-
nous injections of Thioperamide. The following data was obtained from the study:
PROBLEM TABLE 4 - 19. Thioperamide
µg
Time (minutes) mL
3.7 3.1
7.5 2.8
13 2.4
45 1.1
60 0.74
120 0.16
3. Find MRT .
4. Find ( C p )0 .

I.V. Bolus Dosing
(Problem 4 - 19) thioperamide:
101
ConCONCENTRATION (MIC/ML)
100
(ug/mL)
10-1
0 20 40 60 80 100 120
Time (min)
–1
1. k = 0.0254min
2. t½ = 27.3min .
3. MRT = 39.4min .
µg
4. ( C p )0 = 3.39 -------- .
mL
µg ⋅ min
5. AUC = 133.5 --------------------- .
mL
2
µg ⋅ min
6. AUMC = 5256 ----------------------- .
mL
mg
10 -------
Dose kg L
7. Vd = ------------- = -------------------------------------------------------------------- = 2.95 ------
Cp 0 µg mg 1000mL kg
3.39 -------- ⋅ ------------------- ⋅ --------------------
mL 1000µg L
–1 L 1000ml mL
8. Cl = 0.0254min ⋅ 2.95 ------ ⋅ ------------------ = 75 -------------------- .
kg L min ⋅ kg

I.V. Bolus Dosing
Cocaine (Problem 4 - 20)
Khan,vM. et. al. “Determination of pharmacokinetics of cocaine in sheep by liquid chromatography” J. Pharm. Sci. 76:1 (39-43)
Jan 1987

I.V. Bolus Dosing
4.1.3 URINE
From the Laplace Transform of a drug given by IV bolus we find that :
k ( –K ⋅ t )
Xu = ----u- ⋅ X0 ⋅ ( 1 – e ) (EQ 4-10)
K
where Xu is the cumulative amount of drug in the urine at time t. Rearranging, we

get:
k
( Xu )∞ – Xu =  ----u- ⋅ X 0 ⋅ e
– Kt
 K
(EQ 4-11)
ku
where the amount of drug that shows up in the urine at infinite time, ( X u ) ∞ = ----- ⋅ X 0 .
K
Thus a plot of ( Xu )∞ – X u vs. time on semi-log paper would result in a straight line
with a slope of -K and an intercept of ( X u ) ∞ .. and we can get ku from the intercept
( X u )∞
and the slope. Rearranging the intercept equation, we get k u = K ⋅ -------------- This method
X0
of obtaining pharmacokinetic parameters is known as the Amount Remaining to be
Excreted (ARE) method.
TABLE 4-4 Enalapril urinary excretion data from 5 mg IV Bolus
Cumulative
∞
Enalapril in urine X – X u mg
Time (hr) (mg) u
1 0.41 0.59
2 0.65 0.35
3 0.80 0.20
4 0.88 0.12
6 0.96 0.04
∞ 1.0 ------

I.V. Bolus Dosing
Utilizations: A.R.E. FIGURE 4-2. Cumulative Enalapril in urine

Method
10
0
0.2
Xu(inf) - Xu
0.1
-1
10
1.3 hr
half life
-2
10
0 1 2 3 4 5 6
Hours
• You should be able to transform a data set containing amount of drug in the urine vs. time into
cumulative amount of drug in the urine vs. time and plot the ARE. (Amount Remaining to be
Excreted -> { ( Xu )∞ – Xu ( cum ) } vs. time on semi-log yielding a straight line with a slope of
–1 ku ⋅ X0
– K = – 0.533 hr and an intercept of ( Xu ) ∞ = --------------- = 1.0 mg
K
• You should be able to determine the elimination rate constant, K1, from cumulative urinary
excretion data. (Calculate the slope of the graph on SL paper.)
• You should be able to determine the excretion rate constant, ku, from cumulation urinary excre-
tion data. (Divide the intercept of the graph by X0 and multiply by K1.
( X u )∞ –1 1.0 mg –1
k u = K ⋅ -------------- = 0.53 hr ⋅ ----------------- = 0.106 hr )
X0 5.0 mg
• You should be able to determine k m . K = k u + k m

• You should be able to calculate percent metabolized or excreted from a data set. Thus,
km k
Percent metabolized = ------ ⋅ 100 and percent excreted unchanged = ----u- ⋅ 100 assuming
K K
K = k u + km
A second method is to plot the rate at which the drug shows up in the urine over
time. Again, using the LaPlace transforms, we find that:
dX u –K t –K t
--------- = k u ⋅ X0 ⋅ e = R0 ⋅ e (EQ 4-12)
dt
Utilization: Rate of Thus, a plot of the rate of excretion vs. time results in a straight line on semi-log
excretion method paper with a slope of -K1 and an intercept, R0 , of kuX0 . Rearranging the intercept

I.V. Bolus Dosing
R
equation yields k u = -----0- . In real data, we don’t have the instantaneous excretion
X0
dX u ∆X
rate , but the average excretion rate, ---------u- , over a much larger interval. What
dt ∆t
that means to our calculations is that over the interval of data collection, the total
amount of drug collected divided by the total time interval is the average rate. In
the beginning of the interval the rate was faster than at the end of the interval. So
the average rate must have occurred in the middle of the interval. Thus equation 4-
12 which is the instantaneous rate can be rewritten to
∆Xu –K t
mid
–K t
mid
---------- = k u ⋅ X 0 ⋅ e = R0 ⋅ e (EQ 4-13)
∆t
TABLE 4-5 Enalapril Urinary Rate Data
Enalapril in ∆X
urine ∆X u ,(mg) ---------u-
Interval (hr) t(mid) ∆t ∆t
0-1 0.5 1 0.41 0.41
1-2 1.5 1 0.24 0.24
2-3 2.5 1 missed sample ?
3-4 3.5 1 0.08 0.08
4-6 5 2 0.08 0.04
• You should be able to transform a data set containing amount of drug in the urine vs. time inter-
∆X
val into Average Rate, ---------u- , vs. t ,(t mid the time of the midpoint of the interval), on semilog
∆t
yielding a straight line with a slope of – K and an intercept of k u ⋅ X 0 . as shown below.
-1
0
10
R0 = 0.53 mg/hr
Urinary Excretion Rate (mg/hr)
-1
-2
10
1.3 hr
half life
-2
10
0 1 2 3 4 5
T (Mid)
• You should be able to determine k u extrapolate the line to t = 0 . The value of Rate (at
t = 0 ), R0, = k r ⋅ X0 = 0.53 ( mg ⁄ hr ) which when divided by X 0 .is kr.

I.V. Bolus Dosing
R 0.53mg/hr –1
Thus, -----0- = ------------------------- = 0.106hr
X0 5mg
• You should be able to determine k m . K = k u + k m

• You should be able to calculate percent metabolized or excreted from a data set.
The rate equation is superior clinically because the ARE method requires collec-
tion of all of the urine which is usually only possible when you have a catheterized
patient while the Rate Method does not. (People don’t urinate on command, and
your data could be in the toilet, literally.)
∞
An additional advantage of the rate equations is that the AUC has the units of
0
mass, which gives the total amount of drug excreted into the urine directly. Thus:
∞ R 0 0.53 mg/hr
AUC = ------ = --------------------------
–1
= 1 mg
0 K 0.53 hr
AN INTERESTING OBSERVATION: If you look at the LaPlace Transform of the

rate equation for any terminal compartment, you would see that the resulting equa-
tion is that of the previous compartment times the rate constant through which the
drug entered the terminal compartment. Thus, the rate of drug showing up in the
urine (terminal compartment) is:
dX –K t –K t
--------u- = k u ⋅ X 0 ⋅ e = R0 ⋅ e
dt
where ku is the rate constant through which the drug entered the urine and
dX –K t
------- = X 0 ⋅ e is the equation of the previous compartment.
dt

I.V. Bolus Dosing
4.2 Metabolite
4.2.1 PLASMA
Remember, the LaPlace Transform of the metabolite data yielded

( km ⋅ Xo ) –Kt – K 1t ( km ⋅ Xo ) – K 1t – Kt
X m = ---------------------- ⋅ ( e – e ) or Xm = ---------------------- ⋅ ( e – e ) depending on
( K1 – K ) ( K – K1 )
which rate constant that we arbitrarily assigned to be K, the summation of all the
ways that the drug is removed from the body and K1, the summation of all the
ways that the metabolite is removed from the body. When we begin to manipulate
the data, we know that we have a curve with two different exponents in it. (If they
were the same, the equation would be different.) We don’t know which is bigger,
K1 or K, but we can rewrite the equation to simply reflect Klarge and Ksmall, know-
ing that one is K1 and the other is K but not which is which. If we, then, devided
both sides of the equation by Vdm, the volume of distribution of the metabolite,
we would get :
– ( K l arg e ⋅ t )
 km   X 0   – ( Ksmall ⋅ t ) 
C pm =  --------------------------------------  ----------  e –e  (EQ 4-14)
 K l arg e – K small  V dm  
Utilization: • You should be able to plot a data set of plasma concentration of metabolite vs. time on semi-log
Curve Stripping paper yielding a bi-exponential curve.
–k t –k t
– Kt l arg e small
e → 0 as t → ∞ . And e → 0 faster than e → 0 . So, at some long
–K t –K t –K t
l arg e small l arg e
time, t, e «e . In fact e is small enough to be ignored. Thus at long
time, t, the equation becomes :
km X0   –( Ksmall ⋅ t )
C pm =  ----------------------------------
-  --------
- e
K l arg e – K small  V dm   (EQ 4-15)
So that the plot of the terminal portion of the graph would yield a straight line with a slope of
km
 ---------------------------------- X0 
-Ksmall and an intercept of I = -  --------
-
 K l arg e – K small  Vdm
• You should be able to obtain the slope of the terminal portion of the curve, the negative of
which would be the smaller of the two rate constants, K small , (either the summation of all the
ways that the drug is eliminated, K , or the summation of all the ways that the metabolite is
eliminated, K1 ).
• Subtracting the two previous equations yields

I.V. Bolus Dosing
km X 0   –( Kbig ⋅ t )
C pm – C pm =  ----------------------------------
-  --------
- e
K l arg e – K small  Vdm   (EQ 4-16)
which is a straight line on semi-log paper with a slope of -kbig and an intercept of
km X0
I =  ------------------------------------  --------- . Note: we can get the larger of the two rate constants from this
 K l arg e – K small  V dm
method.
TABLE 4-6
Drug Metabolite
(1) (2) (3) (4) (5)
Cp
Time (hr) (mcg/L) Cpm1 (mcg/L) Cpm Cpm – Cpm
0 0 181.2 181.2
0.5 24.7 175 150.3
1 44.4 168.9 124.5
2 139 71.8 157.5 85.7
4 65.6 96.5 136.9 40.4
6 31.1 100 119 19
8 14.6 94.7
12 76.5
24 34
In the above data Cp vs. Time is the plasma profile of the drug from Table 4-1 on page 2 and
Cpm1 vs. Time is the plasma profile of the metabolite. A plot of Cp vs. Time yielded a straight
0.693 –1
line with a slope,(-K) of -0.375 hr-1, K = ---------------------- = 0.375 hr and and intercept of 295 mic/
–1
1.85 hr
L,

I.V. Bolus Dosing
Figure 4-1 on page 3 (column 2 vs. 1 in Table 4-6 on page 53)
10 3
Cpo = 295 mic/L
100
10 2
50
1.85 hr
10 1
0 2 4 6 8
Time (hours)
Time (hr)
while a plot of Cpm1 vs. Time( Figure 4-3 on page 54) yields a biexponential plot with a termi-
nal slope of 0.07 hr-1 , k small = 0.693
------------- and extrapolating the terminal line back to time = 0
10 hr
yields 181 mic/L.
FIGURE 4-3. Nifedipine Metabolite (column 3 vs. 1 in Table 4-6 on page 53)
)
Nifedipine IV bolus - Metabolite

103
mic
Cpm0 = 181 ---------
L
80
102
40
10 hr
101
0 4 8 12 16 20 24
Time (hours)

I.V. Bolus Dosing
• You should be able to feather (curve strip) the other rate constant out of the data by plotting the
difference between the extrapolated (to t = 0 ) terminal line (column 4 vs. 1 in Table 4-6 on
page 53) and the observed data (at early times) (column 3 vs. 1 in Table 4-6 on page 53) yield-
ing a straight line with the slope of the line equal to the negative of the other (larger) rate con-
stant (column 5 vs. 1 in Table 4-6 on page 53).
First you would fill in the Cpm column (column 4 in Table 4-6 on page 53) by computing Cpm
– k small t
for various values of time i.e Cpm = Cpm 0 ⋅ e where – k small is the terminal slope of the
graph. Then Cpm – Cpm (column 5 in Table 4-6 on page 53) would be column 4 - column 3.
Then a plot of Cpm – Cpm vs. time (column 5 vs. 1 in Table 4-6 on page 53) is shown below.
FIGURE 4-4. Curve strip of Nifedipine Metabolite data
10
3
Intercept
2
Column 5
100
102
50 1.85 hr
Half life
1
10
0 1 2 3 4 5 6
Time (hr)
In this case, the slope of the stripped line line is -0.375 hr-1 and the intercept is 0.181.2 mic/L.
The slope of -0.375 hr-1 should not be surprising as the plot of the data in Figure 4-3 on page 54
resulted in a terminal slope of -.07 hr-1 . Since the data set yielded a bi-exponential plot, sepa-
rating out the exponents could only yield K (0.375 hr-1) or K1 as determined by our Laplace
Transform information. Thus, the terminal slope could be either -K1 or -K. Since it was obvi-
ously not -K, it had to be -K1. Thus the other rate constant obtained by stripping has to be K.
You can determine which slope is which rate constant if you have any data regarding intact drug
(i e. either plasma or urine time profiles of intact drug) as the slope of any of those profiles is
always –K .
• You should be able to determine V dm if you have any urine data regarding intact drug (i.e.
urine time profiles of intact drug) as the intercept of those profiles allow for the solution of k m .
Thus the intercept, I, of the extrapolated line of equation 4-14 could be rearranged to contain
–1 1000 mic
km ⋅ X0 0.375hr ⋅ 25mg ⋅ ----------------------
mg
only one unknown variable, V dm = ----------------------------------------------- = -------------------------------------------------------------------------- = 170 L .
( K l arg e – K small ) ⋅ I –1 mic
( 0.375 – 0.07 ) hr ⋅ 181.2 ---------
L

I.V. Bolus Dosing
Utilization: • You should be able to determine the rate constants using MRT calculations.
MRT Calculations In a caternary chain, each compartment contributes its MRT to the overall MRT of the drug,
thus:
Flow Chart 4-4 IV Bolus
K
X
MRT(IV) = 1/K
Suppose the drug were given by IV bolus. Then the drug would have to be metabolized and the
metabolite eliminated. Since the MRTs are additive, the overall MRT of the metabolite would
be made up of the MRTs of the two processes, thus:
Flow Chart 4-5 Metabolite
km kmu
X Xm
MRT(met) = MRT(elim)+MRT(IV)
MRT(met) = 1/K1 + 1/K
Thus, using the data from Table 4-3 on page 5 the MRT(IV)Trap is
------------------ = 1986.1
MRT = AUMC ---------------- = 2.42 hr or about MRT = AUMC
------------------ = 2100
------------ = 2.67 hr using calculus.
AUC 819.9 AUC 787
And using the data from columns 1 and 3 from Table 4-6 on page 53 the MRT(met) using calcu-
------------------ = 36000
lus is MRT = AUMC --------------- = 17 hr.
AUC 2116
MRT(elim) = MRT(met) - MRT(IV) = 17 hr - 2.67 hr = 14.33 hr = 1/K2. Thus K2 = 0.07 hr-1.

I.V. Bolus Dosing
4.2.2 URINE
Valid equations:
dXmu k mu ⋅ k m X0  – K small t – K l arg e t 

------------- = ---------------------------------------- ⋅  e –e  (EQ 4-17)
dt ( K l arg e – K small )  
Utilization: as in the previous urinary rate equation, clinically we work with the average rate
over a definite interval which results in rewriting equation 4-17 as:
∆Xmu k mu ⋅ k m X 0  – Ksmall tmid – K l arg e t mid 

- ⋅ e
------------- = --------------------------------------- –e  (EQ 4-18)
∆t ( K l arg e – K small )  
• You should be able to plot a data set of rate of metabolite excreted vs. time (mid) on semi-log
paper yielding a bi-exponential curve.
• You should be able to obtain the slope of the terminal portion of the curve, the negative of
which would be the smaller of the two rate constants (either K1 or K ).
• You should be able to feather (curve strip) the other rate constant out of the data by plotting the
difference between the extrapolated (to t = 0 ) terminal line and the observed data (at early
times) yielding a straight line with the slope of the line equal to the negative of the other (larger)
rate constant (either K1 or K ).
• You should be able to utilize MRT calculations to obtain K1 and K .
• You should be able to determine which slope is which rate constant if you have any data regard-
ing intact drug (i.e. either plasma or urine time profiles of intact drug) as the slope of any of
those profiles is always –K .
By this time, it should be apparent that data which fits the same shape curve
(mono-exponential, bi-exponential, etc.) are treated the same way. When the
curves are evaluated, the slopes and intercepts are obtained in the same manner.
The only difference is what those slopes and intercepts represent. These represen-
tations come from the equations which come from the LaPlace Transforms which
come from our picture of the pharmacokinetic description of the drug. Please
refer back to the section on graphical analysis in the Chapter 1, Math review for a
interpretation of slopes and intercepts of the various graphs.
Temporarily, please refer to exam section 1, chapter 14 for problems for this sec-
tion (until problems can be generated) as well as additional problems for the previ-
ous sections.

CHAPTER 5 I.V. Infusion

OBJECTIVES
1. Given patient drug concentration and/or amount vs. time profiles, the student will
calculate (III) the relevant pharmacokinetic parameters available ( V d , K, k m , k r ,
AUC , Clearance, MRT) from IV infusion data.
2. I.V. Infusion dosing for parent compounds
3. Plasma concentration vs. time profile analysis
4. Rate vs. time profile analysis
5. Professional communication of IV Infusion information
6. Computer aided instruction and simulation
7. Metabolite (active vs. inactive)

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
I.V. Infusion
5.1 Parent compound
5.1.1 PLASMA
Valid equations:
Q – Kt
C p = -------------- ( 1 – e ) or (EQ 5-1)
K ⋅ Vd
Dose – Kt
-( 1 – e )
C p = -------------------------------------- (EQ 5-2)
K ⋅ Vd ⋅ T infusion
at any time during the infusion
Q
( C p )ss = -------------- (EQ 5-3)
K ⋅ Vd
at steady state (t is long)
– Kt
C p = C p( term ) ⋅ e (EQ 5-4)
after termination of infusion
Where C p is the plasma concentration
Dose is the infusion rate shown in equation 5-1 and equation 5-2.
Q = -------------------
T infusion
Q – Kt infusion
C p( term ) = -------------- ( 1 – e ) is the plasma concentration when the
K ⋅ Vd
infusion is stopped.
Rewriting equation 5-4 to an equation which may be used by a computer results in:
Q - ( e – K ⋅ T∗ – e – K ⋅ T )
Cp = ----------- (EQ 5-5)
K⋅V
where T∗ = ( T – T i v ) for ( T > T iv )
and T∗ = 0 for ( T < T iv ) .

I.V. Infusion
Using The Scientist@‘s Unit function makes the change in T∗ straight forward. In
The Scientist@, Unit(+) = 1 and Unit(-) = 0, so defining T∗ = ( T – T iv ) ⋅ UNIT ( T – Ti v )
meets these needs.
This equation is utilized in The Scientist@’s companion product PKAnalyst@ also

by MicroMath. Since the route of administration is an infusion and we would
know how much we gave (Dose), how fast we gave it (Q), and over how long the
infusion lasted (Tiv), the only other variables in the equation are K and Vd. PKAn-
alyst asks for Tiv and yields DoverV ( Dose

------------- ) and K as parameters resulting from
Vd
non-linear regression analysis. Dividing Dose by Dose

------------- yields Vd.
Vd
Utilization: You should be able to determine the infusion rate necessary to obtain a desired
plasma concentration. Rearranging equation 5-3 results in:
K ⋅ V d ⋅ ( C p )ss = Q (EQ 5-6)
You should be able to determine how long it would take to get to a desired plasma
concentration. Using equation 5-1 and equation 5-3, it looks like it will take for-
ever to get exactly to steady state because in order for
Q = --------------
Q ( 1 – e – Kt ) , e – Kt → 0 which occurs when t = ∞ . So,
( C p )ss = --------------
K ⋅ Vd K ⋅ Vd
how close is close enough? If ( C p ) = 0.95 ⋅ ( C p )ss , that’s good enough in most
people’s estimation. So in order to find out how long it will take we use equation
5-1, setting ( C p ) = 0.95 ⋅ ( C p )ss and solve for time. Thus:
Q ( 1 – e – Kt ) which results in
( C p ) = 0.95 ⋅ ( C p )ss = --------------
K ⋅ Vd
– Kt
0.95 = ( 1 – e )
– Kt
0.95 – 1 = – e
ln ( 0.05 ) = – Kt
– 2.996 = – Kt

I.V. Infusion
–----------------
2.996 = t
–K
2.996
-------------t 1--- = 4.32t 1--- = t , (EQ 5-7)
0.693 2 2
or about 4.32 half lives to get to 95% of steady state. Generalizing, then, the num-
ber of half-lives it takes to get to steady-state is equal to the logarithm of the
inverse of how close is close (in this case, 5% or 0.05 = 20) devided by the loga-
rithm of two.
Changing infusion rates: Occasionally, it is necessary to change infusion rates to stabilize the patient. If a
patient were started on an infusion rate, Q1, and then at some subsequent time,
T>T*, the infusion rate was changed to Q2, the equation for the concentration after
the change would be:
Q1 – ( K ⋅ T∗ ) – ( k ⋅ ( T – T∗ ) ) Q2 - ⋅ ( 1 – e – ( k ⋅ ( T – T∗ ) ) )
Cp = ------------ ⋅ ( 1 – e )⋅e + ----------- (EQ 5-8)
K⋅V K⋅V
Assuming equilibrium was reached at infusion rate Q1, we could simplify equation
5-8 by setting T = 0 at the time of the rate change (thus we would be interested in
the time after the change) resulting in:
Q1 –k ⋅ T Q2 –k ⋅ T
-⋅e
Cp = ----------- + ------------ ⋅ ( 1 – e ) (EQ 5-9)
K⋅V K⋅V
Under these conditions, it would be useful to determine the time to reach the new
equilibrium. As before, within 5% is close enough. Thus if we are coming down
Q2- and if we were
(lowering the Cp, i.e. Q2 < Q1), we would want Cp = 1.05 -----------
K⋅V
Q2 . Taking
going up (raising the Cp, i.e. Q2 > Q1), we would want Cp = 0.95 -----------
-
K⋅V
the first condition we find:
Q2 Q1 –k ⋅ T Q2 - ⋅ ( 1 – e – k ⋅ T )
Cp = 1.05 ------------ = ------------ ⋅ e + ----------- (EQ 5-10)
K⋅V K⋅V K⋅V
Rearranging and solving for T results in:
⋅ Q2
ln  0.05
----------------------
Q1 – Q2 
T = ---------------------------------- (EQ 5-11)
–K
Similarly, under the second condition, we would find:

I.V. Infusion
0.05 ⋅ Q2
ln  –-------------------------
Q1 – Q2 
T = ------------------------------------- (EQ 5-12)
–K
Combining equation 5-11 and equation 5-12 and rearranging results in:
ln  -----------------------
Q1 – Q2- ⋅ 20 ln  ----------------------- Q1 – Q2- ⋅ 20
Q2   Q2 
T = ---------------------------------------------- = ---------------------------------------------- ⋅ t 1 ⁄ 2 (EQ 5-13)
K 0.693
Thus it is the absolute value of the difference of the two rates and the elimination
rate constant which determine the length of time needed to establish a new equilib-
rium. Under the conditions of Q1 = 0 , that is no previous infusion, and the dif-
ference is maximal equation 5-13 simplifies to equation 5-7. Under the conditions
of Q1 = Q2 , the equation is undifined and has no utility (as well as makes no
sense, because the equation was designed to be used when there was a change in
rate.) However, lim T = 0 , thus no change results in zero time to get to the new
Q2 → Q1
equilibium. Similar to equation 5-7 as before, the generalization for the number of
half-lives it takes to obtain the new steady-state is the logarithm of (the fractional
difference of the rates (or the steady-state concentrations) times the inverse of how
close is close) devided by the logarithm of two.
As pharmacokinetic equations are additive, you should be able to determine a
loading dose (by I.V. bolus, for example) and a maintenance dose (infusion rate)
for a patient to extablish an equilibrium. If, for example, you want to give a load-
ing dose followed by an IV infusion, the generalization for the number of half-
lives it takes to obtain the new steady-state is the logarithm of (the fractional dif-
ference of the concentrations, Cp0 and Cpss, times the inverse of how close is
close) devided by the logarithm of two.

I.V. Infusion
Discussion: IV infusion is a controlled way to get drug into your patient. Using patient popula-
tion average pharmacokinetic parameters (K, Vd) available in the drug mono-
graphs, you are able to make a professional judgement about:
1. the plasma concentration that you would like to achieve (from therapeutic range) and the time in
which you would like to get there.
2. the infusion rate necessary to get to the target concentration, and
3. the time necessary to to get there.
Example: Using As an example, theophylline is a bronchodilator used in asthma with a therapeutic

population average range of 10 to 20 mg/L, a volume of distribution of 0.45 (0.3 - 0.7) L/kg and a half
pharmacokinetic life of about 8 (6 - 13) hours for a non-smoking adult. Your patient weighs 200
parameters to make
pounds and meets these these criteria. The physician decides to maintain him at 15
professional judgements.
mg/L. What do you do?
Using population average parameters for K and Vd, equation 5-6 results in:
 0.693 - ⋅  0.45 ----- kg - ⋅ 200 lb ⋅  15 mg

L- ⋅ -------------  = 53.2mg
 ------------   ------- ------- .
8 hr   kg 2.2 lb L hr
For an eight hour IV infusion, you would need
53.2 mg
------- ⋅ 8 hr = 425 mg of theophylline.
hr
IV Theophylline comes as aminophylline which is theophylline compound con-

taining 85% theophylline and 15% ethylenediamine. So in order to get 425 mg of
theophylline we have to give
100 mg aminophylline
425 mg theophylline ⋅ ------------------------------------------------------ = 500 mg aminophylline . So we
85 mg theophylline
prepare our IV infusion using Aminophylline U.S.P. for injection (500 mg amino-
phylline in 20 mL) by placing the contents of the ampule in 1000 mL of D5W and
calculate the drip rate using an adult IV administration set which regulates the drip
to 10 gtts/mL. Thus the drip rate is:
1020 ml- ⋅ ----------------

hr - ⋅ 10 gtts- ∼ 21 --------
gtts- ∼ --------------
7 gtts-
------------------- ---------------
8 hr 60 min ml min 20 sec

I.V. Infusion
How long to get to steady After setting up the infusion, the doctor asks, “How long to steady state?
state?
Using equation 5-7, our patient who has an eight hour half life, will take about
4.32 ⋅ 8 hr = 34.6 hr to get to 95% of steady state. The patient doesn’t want
relief in a day and a half. He needs to breathe NOW. What would you suggest?
Infusion takes too long. It might be possible to give him an IV Bolus dose stat which would get him to
How do we get relief Dose-
now? IV Bolus stat. ( C p )ss right away. This is done by converting ( C p )ss = ------------ to
Vd
V d ⋅ ( C p ) ss = Dose .
 0.45 ----- kg - ⋅ 200 lb ⋅  15 mg

L- ⋅ ------------- ------- = 613.6 mg Theophylline
 kg 2.2 lb   L
Converting to aminophylline yields:

613.6 mg Theophylline ⋅ 100 mg aminophylline ∼ 725 mg aminophylline . Thus,
------------------------------------------------------
85 mg theophylline
if we gave a 725 mg IV bolus dose of aminophylline followed by a concomitant
IV infusion of 500 mg aminophylline over 8 hours, our patient should get to
steady state right away and stay there.
Some protocols require Sometimes the physician might want to just increase the infusion rate (say double
starting with faster it for a short time, 2Q) to get to the target concentration faster and then just back
infusion, then changing the infusion down. If that is the protocol, the question becomes, “ How long do
to a slower one to get to
steady state faster.
you run the infusion in at the faster rate?” Thus:
Q 2Q – Kt – Kt
( C p )ss = -------------- = -------------- ( 1 – e ) which yields 1 = 2 ( 1 – e ) and so
K ⋅ Vd K ⋅ Vd
1 – Kt 1 – Kt
--- = 1 – e . Thus --- – 1 = – e . Taking the ln of both sides ln ( 0.5 ) = –Kt
2 2
ln ( 0.5 ) = 0.693
------------------ ------------- t 1--- = t 1--- = t or that it will take one half-life to get to the target
–K 0.693 2 2
plasma concentration (which is the Cpss obtained by the infusion rate of 1Q) if you
run the infusion at a faster rate, 2Q. So for your patient, you might suggest an
infusion of 1000 mg over 8 hours (2Q for one half life) to get to steady state
quickly and then back off to 500 mg over 8 hours for the second 8 hours.

I.V. Infusion
Clearance: New Clearance ( Cl = K ⋅ Vd ) is a pharmacokinetic parameter which relates the fraction

pharmacokinetic
of the volume of distribution which is cleared of the drug per unit time. The vol-
parameter
ume of distribution is a mathematical construct which relates two knowns, the
Dose of the drug and the resultant Concentration. In linear kinetics, the Dose is
proportional to the Concentration. C ∝ D . The units of concentration are
Mass - while the units of dose are Mass. So the units of the proportionality con-
-------------------
Volume
stant must be volume in order for the equation to balance. Thus, the volume of dis-
tribution is a hypothetical volume and not necessarily a real volume or
physiological space. Consequently, clearance is the hypothetical volume of fluid
from which the drug is irreversibly removed per unit time. So equation 5-3 can be
rewritten:
Q-
( C p )ss = ----- (EQ 5-14)
Cl
How do we calculate and equation 5-14 can be rewritten to:
Clearance from IV infu-
sion data? Q -
Cl = -------------- (EQ 5-15)
( C p )ss
Thus, assuming steady state, the clearance can be calculated by dividing the infu-
sion rate by the resultant steady state plasma concentration.
How do we separate K Graphing equation 5-4 which relates the decline in plasma concentration after ces-
and Vd out of Clear- sation of the infusion, the resultant slope of the line yields - K, the elimination rate
ance? constant. Dividing the elimination rate constant, - K, obtained by equation 5-4 into
the clearance obtained by equation 5-15 results in the other necessary pharmacoki-
netic parameter, Vd.
How can we utilize the From our original model
rate of change of
plasma concentration to d
determine the pharma- X = Q – (K ⋅ X ) (EQ 5-16)
dt
cokinetic parameters, K
and Vd?
X- . Thus , V ⋅ C p = X . Rewriting equation 5-16 yields:
and Cp = ----- d
Vd

I.V. Infusion
dCp Q- – K ⋅ C and rearranging and incorporating equation 5-1 yields

= ----- p
dt Vd
dCp Q- – K ⋅  --------------
Q  ( 1 – e – Kt ) which can be simplified to
= -----
dt Vd  K ⋅ Vd
dCp Q- – ----- Q- e – Kt or
Q- + -----
= -----
dt V d V d Vd
dC p Q- e – Kt
= ----- (EQ 5-17)
dt Vd
vs. t ( actually, ∇
dCp Cp
Thus a plot of ----------- vs. tmid exactly like we did in urinary
dt ∇t
rate graphs) of the ascending portion of the plasma profile would result in a
straight line with a slope of -K and an intercept of ----- Q- .
Vd

I.V. Infusion
5.2 Problems
Equations needed for solving the problems:
1. k from the slope of the terminal portion of the graph of Cp vs. T
0.693
2. t 1 ⁄ 2 = ------------
-
k
3.
Q
Volume of distribution from Cp = -------------- ( 1 – e
– Kt
)
K ⋅ Vd
4. Clearance Cl = K ⋅ V d
5. You wish to maintain a plasma concentration of Cpss.

a. Calculate the infusion rate necessary to maintain
Cpss. Q = Cp ss ⋅ K ⋅ V d
b. Suggest a loading dose which would give you Cpss immediately.
Dose loading = Cp ss ⋅ V d
c. How long will it take to reach steady state?
T 95 = 4.32 ⋅ T 1 ⁄ 2
d. Find the plasma concentration if the infusion is discontinued at time = Tdc hours.
Q ( 1 – e – ( K ⋅ Tdc ) ) .
Cp dc = --------------
K ⋅ Vd
e. Find the plasma concentration Tpost hours after infusion is discontinued at time = Tdc hours.
– ( K ⋅ T post )
Cp post = Cp dc ⋅ e

I.V. Infusion
Acyclovir (Problem 5 - 1)
Problem Submitted By: Maya Leicht AHFS 08:18.00 Antivirals

Laskin, O., "Clinical pharmacokinetics of acyclovir", Clinical Pharmacokinetics (1983), p. 187 - 201.
Acyclovir (225.21 g/Mole) is an antiviral drug used in the treatment of herpes simplex, varicella zoster, and in suppres-
sive therapy. In this study, patients were given varying doses of acyclovir over one hour by infusion. Acyclovir distrib-
utes uniformly into the plasma and tissues such that the plasma concentration is representative of tissue concentration.
Acyclovir is 30% metabolized and 70% renally excreted. The following data was obtained from an intravenous infu-
sion dose of 2.5 mg/kg over one hour where the patient weighed 70 kg.
PROBLEM TABLE 5 - 1. Acyclovir
 umol -
Plasma concentration
 ------------
L
Time (hours)
0 0
0.25 7
0.5 12
0.75 17
1 20
2 10
3 5
5 1
From this data determine the following:

1. k
2. t1 ⁄ 2
3. Volume of distribution
4. Clearance
5. You wish to maintain a plasma concentration of 25 umol ⁄ L .
a. Calculate the infusion rate necessary to maintain a plasma concentration of 25 umol ⁄ L

b. Suggest a loading dose for the patient which would give you Cpss immediately.
d. Find the plasma concentration if the infusion is discontinued at time = 5 hours.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 5 hours.

I.V. Infusion
“Acyclovir” on page 11
102
Concentration
101
100
0 1 2 3 4 5
Time
1. k = 0.751 hr-1 (from slope of graph).
2. t 1 ⁄ 2 = 0.923 hr (from slope of graph).

3. Volume of distribution = 26.2 L
4. Clearance = 19.67 l/hr
5. You wish to maintain a plasma concentration of 25 umol ⁄ L .
a. Calculate the infusion rate necessary to maintain a plasma concentration of 25 umol ⁄ L = 111 mg/hr
b. Suggest a loading dose for the patient which would give you Cpss immediately. 148 mg
c. How long will it take to reach steady state? 4 hr
d. Find the plasma concentration if the infusion is discontinued at time = 5 hours. = 25 umol ⁄ L
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 5 hours. = 5.6 umol ⁄ L

I.V. Infusion
Aminophylline (Problem 5 - 2)
Problem Submitted By: Maya Leicht AHFS 12:12.00 Sympathomimetics

Problem Reviewed By: Vicki Long GPI: 4430001000 Xanthine Sympathomimetic
Gilman, T., et al., "Estimation of theophylline clearance during intravenous aminophylline infusions", Journal of Pharmaceutical
Sciences (May 1985), p. 508 - 514.
Aminophylline is used in the treatment of bronchospasm. In this study, aminophylline was given by intravenous infu-
sion to patients with a mean weight of 75.7 kg. The doses given were chosen to maintain a between 10 -20 mg/L based
on desirable body weight. The doses were given at a rate of 0.5 mg/kg/hour (Theophylline) for 84 hr. The following
set of data was collected.
PROBLEM TABLE 5 - 2. Aminophylline
 mg 
 -------
L
Time (hours)
0 0.
6 5
12 8
24 11
30 11.6
36 12.0
48 12.4
54 12.5
66 12.6
72 12.8
84 12.8
88 9
92 6.4
96 4.6
100 3.2
1. k 2. t1 ⁄ 2
3. Volume of distribution 4. Clearance
5. 6. You wish to maintain a plasma concentration of 15 mg/L in your patient.
a. Calculate the infusion rate necessary to maintain a plasma concentration of 15 mg/L.

I.V. Infusion
“Aminophylline” on page 13
102
CONCENTRATION
101
0
10
0 20 40 60 80 100
Time
1. k = 0.085 hr-1
2. t 1 ⁄ 2 = 8.15 hr
3. Vd = 35.3 L
4. Cl = 3 L/hr
5a. Q = 45 mg/hr
5b. D L = 530 mg
ss
5c. t = 35 hr
95%
5d. C p = 5.2 mg/L
5e. C p = 4.4 mg/L

I.V. Infusion
Carmustine (Problem 5 - 3)
Problem Submitted By: Maya Leicht AHFS 10:00.00 Antineoplastics

Problem Reviewed By: Vicki Long GPI: 2110201000 Antineoplastics, Nitrosoureas
Henner, W., et al., "Pharmacokinetics and immediate effects of high-dose carmustine in man", Cancer Treatment Reports vol.70
(1986), p. 877 - 880.
Carmustine (BCNU) is an antineoplastic agent with a molecular weight of 214.04 g.

2
In this study a 70 kg, 1.8 M2 patient was given 600 mg ⁄ m by intravenous infusion over 2 hours. The following data
was obtained.
PROBLEM TABLE 5 - 3. Carmustine
mg
Plasma concentration -------
Time (minutes) L
15 .3
30 .5
60 .7
90 .75
120 .8
135 .5
142.5 .4
150 .3

1. k
2. t1 ⁄ 2
3. Vd
4 Cl
2
5. A patient with a BSA of1.8 M is to be given BCNU by IV infusion. You wish to maintain a plasma
concentration of 2 uM . Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 2 uM .

d. Find the plasma concentration if the infusion is discontinued at time = 10 minutes.
e. Find the plasma concentration 1 hour after infusion is discontinued at time = 10 minutes.

I.V. Infusion
“Carmustine” on page 15
0
10
CONCENTRATION
-1
10
0 50 100 150
TIME
1. k = 0.031 min-1
2. t 1 ⁄ 2 = 22 min
3. Vd = 198 L/M2
4 Cl = 6.15 L/M2/hr
2
5. A patient with a BSA of1.8 M is to be given BCNU by IV infusion. You wish to maintain a plasma
concentration of 2 uM . Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 2 uM .
Q = Cp ss ⋅ V d ⋅ K = 2µmole 214µg- ⋅ ------------------

mg - ⋅ ------------
198L ⋅ 1.8M 2 ⋅ 0.031min– 1 = 4.73mg
------------------- ⋅ --------------- ------------------ ∼ 285mg
-----------------
L µmole 1000µg M2 min hr
Dose = Cp ss ⋅ Vd = 2µmole 214µg- ⋅ ------------------
mg - ⋅ ------------
198L ⋅ 1.8M 2 = 150mg
------------------- ⋅ ---------------
L µmole 1000µg M 2
c. How long will it take to reach steady state? 4.32 * T 1/2 = 97 min.
d. Find the plasma concentration if the infusion is discontinued at time = 10 min. = 0.1197 mg/L
e. Find the plasma concentration 1 hour after infusion is discontinued at time = 10 min. = 0.017 mg/L

I.V. Infusion
Cefotaxime (Problem 5 - 4)
Problem Submitted By: Maya Leicht AHFS 08:12.06 Cephalosporins

Problem Reviewed By: Vicki Long GPI: 0230007510 Cephalosporins - 3rd Generation
Kearns, G., Young, R., and Jacobs, R., "Cefotaxime dosage in infants and children--pharmacokinetic and clinical rationale for an
extended dosage interval", Clinical Pharmacokinetics (1992), p. 284 - 297.
Cefotaxime is a third generation cephalosporin which is widely used as an antimicrobial in neonates, infants, and chil-
dren. In this study, infants and children were given a 50 mg/kg dose of cefotaxime intravenously over 0.25 hour. The
following data was collected:
PROBLEM TABLE 5 - 4. Cefotaxime
 mg 
 -------
L
Time (hours)
0.00 0
0.05 35
0.10 70
0.20 140
0.35 155
0.60 130
0.85 110
1.20 80
1.30 75
2.00 45
2.40 35
3.40 15
4.50 8
6.50 1.7
From this data, assuming that the patient weighs 30 kg, determine the following:
1. k
2. t1 ⁄ 2
3. Vd
4. Cl
5. You wish to maintain a plasma concentration of 80 mg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 80mg/L
d. Find the plasma concentration if the infusion is discontinued at time = 0.25 hours.

I.V. Infusion
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 0.25 hours.
“Cefotaxime” on page 17
103
CONCENTRATION
102
101
100
0 1 2 3 4 5 6 7
TIME
1. k = 0.733 hr-1
2. t 1 ⁄ 2 = 0.945 hr
3. Vd = 0.276 L/kg
4. Cl = 0.202 L/kg/hr
4a. Q = 16.2 mg/kg/hr

4b. D L = 22.1 mg/kg
ss
4c. t = 4.1 hr
95%
4d. C p = 13.35 mg/L
4e. C p = 3.09 mg/L

I.V. Infusion
Ganciclovir (Problem 5 - 5)
Problem Submitted By: Maya Leicht AHFS 08:18.00 Antivirals

Trang, J., et al., "Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections",
Clinical Pharmacology and Therapeutics (1993), p. 15 - 21.
Ganciclovir is used against the human herpes viruses, cytomegalovirus retinitis, and cytomegalovirus infections of the
gastrointestinal tract. In this study, twenty-seven newborns with cytomegalovirus disease were given 4 mg/kg of ganci-
clovir intravenously over one hour. Blood samples were taken and the data obtained is summarized in the following
table:
PROBLEM TABLE 5 - 5. Ganciclovir
Plasma concentration  --------

ug
 mL
Time (hours)
0.5 3.10
1.5 4.50
2.0 3.80
3.0 2.90
4.0 2.30
6.0 1.50
8.0 0.88

1. k
2. t1 ⁄ 2
3. Vd
4. Cl
4. A patient is to be given ganciclovir by IV infusion to an infant weighing 6.1 kg. You wish
to maintain a plasma concentration of 5.5 mcg/mL. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 5.5mcg/mL.
d. Find the plasma concentration if the infusion is discontinued at time = 1 hour.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 1 hour.

I.V. Infusion
“Ganciclovir” on page 19
10 1
CONCENTRATION
10 0
10-1
0 2 4 6 8
Time
1. k = 0.255 hr-1
2. t 1 ⁄ 2 = 2.72 hr
3. Vd = 0.687 L/kg
4. Cl = 0.175 L/kg/hr
1000ml ⋅  0.687L
Q = Cp ss ⋅ V d ⋅ K = 5.5µg - ⋅ 6.1kg ⋅ 0.255
mg - ⋅ ------------------
-------------- ⋅ ------------------ ------------- = 5.9mg
 ----------------
5a. ---------------
ml 1000µg L kg hr hr
1000ml ⋅  0.687L
D L = Cp ss ⋅ Vd = 5.5µg ----------------- ⋅ 6.1kg = 23mg
mg - ⋅ ------------------
5b. -------------- ⋅ ------------------
ml 1000µg L  kg 
ss
5c. T = 4.32 ⋅ t1 ⁄ 2 = 11.75hr
95%
5.9mg
---------------
Q hr – K ⋅ 1hr
) = 1.24mg
– Kt
5d. C p term = -------------- ( 1 – e ) = -----------------------------------------------------
- (1 – e ------------------
K ⋅ Vd 0.255
------------- ⋅ 0.687L L
----------------- ⋅ 6.1kg
hr kg
– K ⋅ 2hr
5e. C p = C p term ⋅ e = 1.24mg
------------------ ⋅ 0.6 = 0.74mg
------------------
L L

I.V. Infusion
Gentamicin (Problem 5 - 6)
Problem Submitted By: Maya Leicht AHFS 00:00.00

Problem Reviewed By: Vicki Long GPI: 0700002010 Aminoglycosodes
Kaojarern, S., et al., "Dosing regimen of gentamicin during intermittent peritoneal dialysis", Journal of Clinical Pharmacology
(1989), p. 140 - 143.
Gentamicin is an aminoglycoside antibiotic which is frequently used in the treatment of gram-negative bacilli infec-
tions. Since it has a low therapeutic index, it is important to determine proper dosage regimens. In this study, patients
on peritoneal dialysis received a 30 minute intravenous infusion of 80 mg gentamicin in 100 mL of 5% dextrose in
water. The following data was collected:
PROBLEM TABLE 5 - 6. Gentamicin
 -------
ug 
 mL-
Time (hours)
0.50 5.68
1.50 5.15
3.70 4.80
7.35 3.99
11.30 3.35
24.00 2.02

1. k
2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given gentamicin by IV infusion. You wish to maintain a plasma concentration
of 5.2 ug ⁄ mL . Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 5.2 ug ⁄ mL

d. Find the plasma concentration if the infusion is discontinued at time = 0.5 hours.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 0.5 hours.

I.V. Infusion
“Gentamicin” on page 21
101
CONCENTRATION
100
0 5 10 15 20 25
Time
1. k = 0.0431 hr-1
2. t 1 ⁄ 2 = 16.1 hr
3. V d = 14.5 L
4. Cl =0.625 L/hr
5a. Q = 3.25 mg/hr

5b. D L = 75 mg
ss
5c. t = 69.6 hr
95%
5d. C p = 0.11 mg/L
5e. C p = 0.10 mg/L

I.V. Infusion
Human Monoclonal Anti-lipid A antibody (HA-1A) (Problem 5 - 7)
Problem Submitted By: Maya Leicht AHFS 24:06.00 Antilepemics

Problem Reviewed By: Vicki Long GPI: 3900000000 Antihyperlipidemic
Fisher, C., et al., "Initial evaluation of human monoclonal anti-lipid A antibody (HA-1A) in patients with sepsis syndrome", Criti-
cal Care Medicine (1990), Vol.18, No. 12, p. 1311 - 1315.
HA-1A is an immunoglobulin antibody. In this study, patients received a 250 mg intravenous infusion of HA-1A over
15 minutes. Serum levels were measured before and after infusion and the following data was collected:
PROBLEM TABLE 5 - 7. Human Monoclonal Anti-lipid A antibody (HA-1A)
Plasma concentration  -------

ug-
 mL
Time (hours)
0.00 0
0.75 80
1.00 75
2.00 74
5.00 65
15.00 50
25.00 40
48.00 21
72.00 10

1. k
2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given HA-1A by IV infusion. You wish to maintain a plasma concentration of 100 µg/mL.
Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 100 ug ⁄ mL .


I.V. Infusion
“Human Monoclonal Anti-lipid A antibody (HA-1A)” on page 23

102
CONCENTRATION
101
0 20 40 60 80
Time
1. k = 0.0282 hr-1
2. t 1 ⁄ 2 = 24.4 hr
3. V d = 3.2 L
4. Cl = 0.09 L/hr
5a. Q = 9 mg/hr
5b. D L = 320 mg
ss
5c. t = 105 hr
95%
5d. C p = 2.78 mg/L
5e. C p = 2.56 mg/L

I.V. Infusion
Ifosfamide (Problem 5 - 8)

Problem Reviewed By: Vicki Long GPI: 0000000000
Lewis, L., "The pharmacokinetics of ifosfamide given as short and long intravenous infusions in cancer patients", British Journal
of Clinical Pharmacology Vol. 31 (1991), p. 77 - 82.
Ifosfamide is an agent which has shown some pharmacological response in the treatment of cancer. In this study, a 5
2 2
g⁄m dose of ifosfamide was infused over 30 minutes. The median BSA for the subjects was 1.8 m . The
following data was obtained:
PROBLEM TABLE 5 - 8. Ifosfamide
 -------
ug 
 mL-
Time (hours)
0 0.0
0.5 285.0
1 260.0
2 220.0
4 160.0
6 112.0
8 80.0
10 60.0
24 5

1. k
2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given ifosfamide by IV infusion. The patient has a BSA 1.8 M2. You wish to maintain a
plasma concentration of 336 µg/mL. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 336 ug ⁄ mL

d. Find the plasma concentration if the infusion is discontinued at time = 20 min.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 20min.

I.V. Infusion
“Ifosfamide” on page 25
103
102
CONCENTRATION
101
100
0 5 10 15 20 25
Time
1. k = 0.1716 hr-1
2. t 1 ⁄ 2 = 4.04 hr
3. V d = 16.6 L/M2
4. Cl = 2.85 L/hr/M2
5a. Q = 1.725 g/hr
5b. D L = 10 g
ss
5c. t = 17.5
95%
5d. C p = 18.7 mg/L
5e. C p = 13.25 mg/L

I.V. Infusion
Isosorbide 5-mononitrate (Problem 5 - 9)

Major, R., et al., "Isosorbide 5-mononitrate kinetics" (1983), p. 653- 660.
Isosorbide 5-mononitrate (5-ISMN) is a metabolite of isosorbide dinitrate. In this study, the kinetics of isosorbide 5-
mononitrate were looked at in 12 healthy patients after an intravenous infusion of 20 mg at 8 mg/hour for 2.5 hours.
This drug follows one-compartment, open model kinetics. The following data was collected:
PROBLEM TABLE 5 - 9. Isosorbide 5-mononitrate
Time (hours) Plasma concentration (ng/mL)

0.25 40
0.50 91
0.75 141
1.00 181
1.50 239
2.00 305
2.50 351
3.00 335
3.50 303
4.50 257
5.50 216
7.50 162
9.50 117
11.50 77
14.50 47
18.50 24
26.50 7

1. k 2. t1 ⁄ 2
3. Vd 4. Cl
5. A patient is to be given 5-ISMN by IV infusion. You wish to maintain a plasma concentration
of 300 ng/mL. If the volume of distribution of 5-ISMN is 44.5, determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 300 ng/mL.

I.V. Infusion
“Isosorbide 5-mononitrate” on page 27

103
CONCENTRATION
102
101
100
0 5 10 15 20 25 30
Time
1. k = 0.168 hr-1
2. t 1 ⁄ 2 = 4.125 hr
3. V d = 44.6 L
4. Cl = 7.5 L/hr
5a. Q = 2.25 mg/hr
5b. D L = 13.4 mg
ss
5c. t = 17.8 hr
95%
5d. C p = 46.4 ng/mL
5e. C p = 33.2 ng/mL

I.V. Infusion
Moclobemide (Problem 5 - 10)

Schoerlin, M., et al., "Disposition kinetics of moclobemide a new MAO-A inhibitor, in subjects with impaired renal function", Jour-
nal of Clinical Pharmacology Vol 30 (1990), p. 272 - 284.
Moclobemide is reversibly inhibits the A-isozyme of the monoamine oxidase enzyme system. In this study, twelve
patients received a 96.7 mg dose as an intravenous infusion over 20 minutes. Blood samples were obtained during the
infusion and after the infusion was ended and the following data was obtained:
PROBLEM TABLE 5 - 10. Moclobemide
Time (hours) Plasma concentration (mg/L)

0.0 0.000
0.2 0.6
0.4 1
0.7 0.85
0.9 0.750
1.2 0.70
1.6 0.60
1.9 0.50
2.4 0.40
3.4 0.25
4.5 0.15
5.5 0.10
6.4 0.070

1. k
2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given moclobemide by IV infusion. You wish to maintain a plasma concentration
of 1mg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 1mg/L.
d. Find the plasma concentration if the infusion is discontinued at time = 15 min.

I.V. Infusion
e. Find the plasma concentration 3 hours after infusion is discontinued at time = 15 mins.
“Moclobemide” on page 29
10 0
CONCENTRATION
10-1
10-2
0 1 2 3 4 5 6 7
Time
1. k = 0.44 hr-1
2. t 1 ⁄ 2 = 1.6 hr.
3. V d = 90.4 L
4. Cl = 39.8 L/hr
5a. Q = 40 mg/hr
5b. D L = 90 mg
ss
5c. t = 6.8 hr
95%
5d. C p = 0.1 mg/L
5e. C p = 0.028 mg/L

I.V. Infusion
Obidoxime (Problem 5 - 11)

Bentur, Y., et al., "Pharmacokinetics of obidoxime in organophosphate poisoning associated with renal failure", Clinical Toxicol-
ogy (1993), Vol. 31, p. 315 - 322.
Obidoxime is an agent which is used as an antidote in organophosphate poisoning. In this study, the pharmacokinetics
of obidoxime were studied in a 20 year old patient who attempted to commit suicide by ingesting Tamaron (60% meth-
amidophos, an organophosphate, in ethylene glycol monethyl ether). She was given 4 mg/kg Obidoxime by intrave-
nous infusion over 10 minutes and the following data was collected:
PROBLEM TABLE 5 - 11. Obidoxime
Time (minutes) Plasma concentration µg ⁄ mL

5 9
10 18
15 17
30 16
45 15
60 14
90 12
120 11
150 9.3
180 8
240 6.1
300 4.6

1. k
2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given obidoxime by IV infusion. The patient has a body weight of 60 kg.
You wish to maintain a plasma concentration of 10 µg/mL. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 10 ug ⁄ mL .

I.V. Infusion
e. Find the plasma concentration 1 hour after infusion is discontinued at time = 30 minutes.
“Obidoxime” on page 31
102
CONCENTRATION
101
100
0 50 100 150 200 250 300
Time
1. k = 0.00463 min-1
2. t 1 ⁄ 2 = 150 min
3. V d = 0.22L/kg
4. Cl = 1 mL/min
5a. Q = 0.61 mg/min
5b. D L = 132 mg
ss
5c. t = 10.8 hr
95%
5d. C p = 1.3 mg/L
5e. C p = 0.98 mg/L

I.V. Infusion
Perindoprilat (Problem 5 - 12)

Macfadyen, R., Lees, K., and Reid, J., "Studies with low dose intravenous diacid ACE inhibitor (perindoprilat) infusions in normo-
tensive male volunteers", Journal of Pharmaceutical Sciences (1991), p. 115 - 121.
Perindoprilat and other ACE inhibitors are used in the management of hypertension and chronic congestive heart fail-
ure. In this study, a 1 mg dose was infused over a one hour period. The following data was collected:
PROBLEM TABLE 5 - 12. Perindoprilat
Time (minutes) Plasma concentration ng ⁄ mL

5 4.0
10 9.0
20 16.0
30 24.0
40 30.0
50 36.0
60 42.0
65 40.0
70 38.0
80 35.0
90 32.0
100 29.0
110 27.0
120 24.0

1. k
2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given perindoprilat by IV infusion. You wish to maintain a plasma concentration
of 30 ng/ml. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 30 ng/mL.

I.V. Infusion
“Perindoprilat” on page 33
102
CONCENTRATION
101
100
0 20 40 60 80 100 120
Time
1. k = 0.0087 min-1
2. t 1 ⁄ 2 = 79.6 min
3. V d = 18.9 L
4. Cl =164 mL/min
5a. Q = 5 µg/min
5b. D L = 0.57 mg
ss
5c. t = 5.73 hr
95%
5d. C p = 27.8 ng/mL
5e. C p = 9.8 ng/mL

I.V. Infusion
Sulfonamides (Problem 5 - 13)

Boddy, A., Edwards, P., and Rowland, M., "Binding of sulfonamides to carbonic anhydrase: influence on distribution within blood
and on pharmacokinetics", Pharmaceutical Research (1989), p. 203- 209
This study looks at the affinity of sulfonamides for carbonic anhydrase. Doses of 8 micromoles/kg were administered
via the jugular vein cannula in approximately 0.5 mL of PEG 400 over 5 minutes at a constant rate. Samples were col-
lected during the infusion period and for 30 minutes afterward. The following set of data was collected:
PROBLEM TABLE 5 - 13. Sulfonamides
Time (minutes) Plasma concentration ( µM )

2.0 17.0
4.0 31.0
5.0 37.0
7.5 32.0
9.0 28.0
12.0 22.5
15.0 18.0
18.0 14.0
23.0 11.0
30.0 6.5
35.0 4.5

1. k
2. t1 ⁄ 2
3. Vd
4. Cl
5. A 70-kg patient is to be given a sulfonamide by IV infusion. You wish to maintain a plasma
concentration of 30 µM. Determine the following:
a. Calculate the infusion rate which would be necessary to maintain the plasma concentra-
tion of 30 µM.

I.V. Infusion
e. Find the plasma concentration 30 minutes after stopping infusion at time = 4 hours.
“Sulfonamides” on page 35
102
CONCENTRATION
101
100
0 5 10 15 20 25 30 35
Time
1. k = 0.0705 min-1
2. t 1 ⁄ 2 = 9.8 min
3. V d = 0.18 L/kg
4. Cl = 12.7 mL/min/kg
5a. Q = 26.9 µmole/min
5b. D L = 380 µmole
ss
5c. t = 42 min
95%
5d. C p = 30 µmole/L
5e. C p = 3.6 µmole/L

I.V. Infusion
Terodiline (Problem 5 - 14)

Hallen, B. ,et al., "Bioavailability and disposition of terodiline in man", Journal of Pharmaceutical Sciences (1994), p. 1241 -
1246.
Terodiline is an agent which works as an anticholinergic and a calcium antagonist. It is used to treat incontinence. It
is metabolized into p-Hydroxyterodiline, which is further metabolized to 3,4-dihydroxyterodiline. The parent drug and
all of its metabolites are excreted into the urine as well as the feces. A patient is given 12.5 mg of Terodiline by IV
infusion at a rate of 1 mL/ minute for 5 minutes. The following data is collected:
PROBLEM TABLE 5 - 14. Terodiline
Time (hours) Plasma concentration µg ⁄ L

25.000 31
50.000 23
75.000 15
100.000 12
125.000 8
150.000 6
175.000 4
200.000 3
225.000 2

1. k
2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given terodiline by IV infusion. You wish to maintain a plasma concentration
of 40 mcg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain the plasma concentration of40 mcg/L.
e. Find the plasma concentration 2 hours after stopping infusion if the infusion ended at
time = 5 hours.

I.V. Infusion
“Terodiline” on page 37
102
CONCENTRATION
101
100
0 50 100 150 200 250
Time
1. k = 0.0136 hr-1
2. t 1 ⁄ 2 = 50.9 hr
3. V d = 283 L
4. Cl =3.85 L/hr
5a. Q = 0.154 mg / hr
5b. D L = 11.32 mg
ss
5c. t = 220 hr
95%
5d. C p = 2.63 µg/L
5e. C p = 2.56 µg/L

I.V. Infusion
Tinidazole (Problem 5 - 15)

Robson, R., Bailey, R., and Sharman, J., "Tinidazole pharmacokinetics in severe renal failure", Clinical Pharmacokinetics (1984),
p. 88 - 94.
Tinidazole is an antimicrobial similar to metronidazole which is used in the treatment of trichomoniasis, giardiasis,
amoebiasis, and anaerobic infections. This study focuses on the pharmacokinetics of tinidazole in patients suffering
from severe renal failure. Twelve patients received 800 mg of tinidazole dissolved in 400 mL of dextrose monohydrate
solution as an intravenous infusion at a rate of 60 mg/min. Blood samples were taken and the following data was
obtained:
PROBLEM TABLE 5 - 15. Tinidazole
Time (hours) Plasma concentration (mg/L)

1 14.9
3 13.1
6 11.2
12 8.9
24 5.1
48 2.1

1. k
2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given tinidazole by IV infusion. Determine the following:
a. Calculate the infusion rate necessary to maintain the plasma concentration of 25 mg/L.
e. Find the plasma concentration 2 hours after stopping infusion if the infusion was stopped
at time = 1 hour.

I.V. Infusion
“Tinidazole” on page 39
102
CONCENTRATION
101
100
0 10 20 30 40 50
Time
1. k = 0.04136 hr-1
2. t 1 ⁄ 2 = 16.75 hr
3. V d = 54.7 L
4. Cl = 2.26 L/hr
5a. Q = 56.6 mg/hr
5b. D L = 1.37 g
ss
5c. t = 72.4 hr
95%
5d. C p = 1 mg/L
5e. C p = 0.93 mg/L

I.V. Infusion
Tobramycin (Problem 5 - 16)

Cooney, G., et al., "Absolute bioavailability and absorption characteristics of aerosolized tobramycin in adults with cystic fibro-
sis", Journal of Clinical Pharmacology Vol. 34, (1994), p. 255- 259.
Most persons with cystic fibrosis (CF) become colonized with Pseudomonas aeruginosa in their bronchial secretions
within their second decade of life. These patients require frequent treatment with potent anti-pseudomonal antibiotics
such as Tobramycin. In this study, an intravenous infusion of 2.5 mg/kg tobramycin was given over 35 minutes. The
following data was collected:
PROBLEM TABLE 5 - 16. Tobramycin
 mg 
 -------
L
Time (minutes)
35 8.00
60 6.00
90 4.50
150 2.50
270 0.75

1. k
2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given tobramycin by IV infusion. The patient has a body weight of 70 kg. You wish
to maintain a plasma concentration of 10 mg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain the plasma concentration of 10 mg/mL.
e. Find the plasma concentration 1 hour after stopping infusion if the infusion wasstopped at
time = 30 minutes.

I.V. Infusion
“Tobramycin” on page 41
101
CONCENTRATION
100
10-1
0 50 100 150 200 250 300
Time
1. k = 0.01 min-1
2. t 1 ⁄ 2 = 69.3 min
3. V d = 0.269 L/kg
4. Cl = 2.7 mL/min
5a. Q = 0.027mg/kg/min = 1.62 mg/kg/hr
5b. D L = 2.7 mg/kg
ss
5c. t = 300 min = 5 hr
95%
5d. C p = 2.6 mg/L
5e. C p = 1.43 mg/L

CHAPTER 6 Biopharmaceutical Factors
Author: Michael Makoid

OBJECTIVES
After successfully completing this chapter, the student shall understand:
1. Physiology and machanisms of absorbtion
2. Effects of diffusion, cardiac output / blood perfusion, physical properties of the
drug and body on distribution
3. Biotransformation, first pass effect, and clearance
4. Renal, biliary, mammary, salivary, other forms of excretion.
5. identify the effects of physiological changes with age, sex, and disease on the
absorption, distribution, metabolism, and excretion of a drug.

CHAPTER 7 Oral Dosing

OBJECTIVES
After successfully completing this chapter, the student shall be able to
1. Given patient drug concentration and/or amount vs. Time profiles, the student will
calculate (III) the relevant pharmacokinetic parameters ( V d , K, k m , k r , k a , AUC ,
Clearance, MRT, MAT) available from oral data.
calculate (III) the K from the terminal portion of the curve.
calculate (III) the k a from either the curve stripping Moment techniques.
calculate (III) the Absolute Bioavailability from comparing IV and oral (or
some other process which involves absorption) data.
calculate (III) the Comparative Bioavailability from comparing the generic to the
inovator product.
qualitatively evaluate (IV) bioequivalence as determined by rate of absorption
(peak time) and extent of absorption (Area Under the Curve - AUC, and ( Cp ) max ).
evaluate (IV) bioequivalence data.
lucidly discuss (IV) bioequivalence and recommend (V) to another competant
professional if s/he believes products to be equivalent.

Oral Dosing
9. The student shall be able to properly use vocabulary relative to bioequivalence.

Oral Dosing
7.1 Oral dosing
7.1.1 VALID EQUATIONS: ( ORAL DOSING, PLASMA)
ka –k t
C p = fD
– Kt
------ ⋅ --------------
- ⋅ (e – e a ) (EQ 5-18)
Vd k a – K
AUC ( oral ) ⁄ Dose ( oral )

f = -------------------------------------------------------------- (EQ 5-19)
AUC ( iv ) ⁄ Dose ( iv )
AUC ( generic ) ⁄ Dose ( generic ) -

CB = ------------------------------------------------------------------------------------- (EQ 5-20)
AUC ( inovator ) ⁄ Dose ( inovator )
ln ( k a ⁄ K )
t p = ----------------------- (EQ 5-21)
( ka – K )
X
-----a- = K ⋅ AUC ∞ – ( C p + K ⋅ AUC t ) (EQ 5-22)
v
where CB = the comparative bioavailability
f = the absolute bioavailabilty; the fraction of dose which ultimately reaches sys-
temic circulation (which is made up of the fraction of the dose which is absorbed
times the fraction which gets past the liver (first pass effect))
ka = absorption rate constant.
7.1.2 UTILIZATION

Oral Dosing
Ampicillin (Problem 5 - 17)
The following information is available for ampicillin: 90% is excreted unchanged and a 250 mg IV bolus dose yields an
AUC of 11 mic/mL*hr. The following blood level profile has been reported for two brands of ampicillin which were
given as 500 mg oral capsules.
TABLE 4-7
µg
MEAN SERUM LEVEL --------
Time (hr) mL
LEDERLE BRISTOL
0.5 0.37 0.38
1.0 1.97 1.91
1.5 2.83 2.49
2.0 3.15 3.11
3.0 2.73 2.79
4.0 1.86 1.95
6.0 0.43 0.49
Find the following:.

a. k for both products.
b. k a for both products.
c. k u for both products.
d. AUC for both products.

e. f for both products.
f. t max for both products.
g. Cl
h. Vd
i Cp 0 for a 250 mg IV dose.
j. Cp max
k. Are these two products bioequivalent? Why or why not?

l. What infusion rate would be necessary to maintain a serum

Oral Dosing
plasma concentration of 2mcg/mL
The data was plotted as above with the best fit line drawn. From the graph the fol-
lowing parameters were derived:
TABLE 4-8 Comparison of Ampicillin
Lederle Bristol Ratio (L/B)

–1 0.688 0.635
K ( hr )
–1 0.858 0.831
K a ( hr )
T max ( hr ) 1.74 1.8 0.97
( C p ) max ( µg ⁄ mL ) 3 2.9 1.03
AUC (trapaziodal) 11.4 11.6 0.98
2) In a clinical study (DiSanto & DeSante, JPS 64:100,1975) prednisone was

administered to 22 adult healthy volunteres (average weight 64.5 kg) either as one
50 mg tablet (product A) or as ten 5 mg tablets (product B). The following data
was observed:
Time (hours) Concentration (mic/100ml plasma)
A B

Oral Dosing
0.5 40.8 57.3
1 70.0 77.1
2 79.5 82.3
3 80.7 69.4
4 68.6 60.6
6 49.4 48.0
8 35.0 33.7
12 15.3 17.4
24 2.1 3.0
Find ka's for both products.
Calculate peak time and Cp max and AUC for both products.
Can you conclude that these products are bioequivalent ?
(Reasons should include discussion of rate and extent of absorption)
Answer:

Oral Dosing
Product A Product B Ratio (A/B)
Ka (hr^-1) 1.19 1.8
Tmax (hr) 2 1.52 1.31
Cmax (mcg/100mL)83.2 82.8 1.00
AUC (trapazoidal)676.52 688.81 0.976
Can you conclude that these products are bioequivalent ?
No, Time to peak (Tmax) is outside guidelines.
3) Wilkenstein et al.(Gastroenterology 74:360,1978) tested 12 normal healthy

volunteers in a four way crossover design of four dosage forms containing 300 mg
of cimetadine. The following data was obtained:

Oral Dosing
A B C D
A.U.C. (mic/ml x hr)------ 5.2 5.4
% recovered in urine intact77.177.147.149.0
Peak serum conc.(mic/ml)------ 1.53 1.44
Onset (hr) 0 0.34 0.65
Duration (hr) 4.5 4.0 4.2 4.4
Time to peak (hr)0 1.0 2.0
A = IV bolus B = IM inj. C = Oral Liq. D = Oral Tab.
The plasma concentration - time profile for product A is as follows:
time(hrs) (ug/ml) time(hrs) (ug/ml)
1 1.79 6 0.45
2 1.36 12 0.08
4 0.78
a} Using linear regression, find K & Cp0.
b} What is the absolute bioavailability (f) of the liquid.
c} How does that correlate with % recovered intact in the urine?
d} Would you consider the oral forms bioequivalent?
Why/Why not?

Oral Dosing
f} What infusion rate would you suggest to maintain a plasma concentration of

0.75 mic/ml ?
g} How long would it take that infusion rate to attain a therapeutic plasma con-
centration of 0.5 mic/ml ?
Answer:
IV Bolus Parameters:
Cp max2.4 mic/mL
AUC 8.5
K 0.283 hr^-1

Oral Dosing
a} Using linear regression, find K & Cp0. (graph)
5/2/8.5 = 0.61
Very well. Only 61% (f) of liquid gets in and you would expect only 77% of that to
show up in the urine because only 77% of the IV dose shows up in the urine
(.61*.77=.47).
d} Would you consider the oral forms bioequivalent? (No)
Why/Why not? Ratio of peak times ouside guidelines.
e} What infusion rate would you suggest to maintain a plasma concentration of

0.75 mic/ml ?
Q = Cpss * K * V = 0.75 mg/L * 0.283 hr^-1 * 125 L = 26.54 mg/hr
f} How long would it take that infusion to attain a therapeutic plasma concentra-
tion of 0.5 mic/ml ?
Cp = Q/(K*V)(1-exp(-K*T) = 0.5 = 26.54/(0.283*125)*(1-exp(-0.283*T)) --> 3.9

hr
4) LYSERGIC ACID DIETHYLAMIDE (LSD) was given to human volunteers at

the dose of 150 mic orally. (Impregnated blotter dosage form.) The following data
was obtained:

Oral Dosing
Time Cp (ng/ml) Time Cp (ng/ml)
0.25 1.75 2.0 4.6
0.5 2.9 3.0 4.1
0.75 3.7 4.0 3.3
1.0 4.2 6.0 2.1
1.5 4.6 8.0 1.4
a) Find ka
b) An IV dose of 100 mic resulted in an AUC of 20.4 ng/ml*hr. Find f.
c) The volunteers ability to concentrate as measured by their ability to do standard

tasks was also monitored. (100% control means no drug interference.) The fol-
lowing data was obtained:
Cp (ng/ml) % Control Cp (ng/ml) % Control
5.5 33 1.5 65
4.1 40 1.1 80
2.9 52
If 100 mic dose were given by IV bolus, how long would it be before the volunteer
would regain 80% of his control?
Answwer:

Oral Dosing
Evaluation of the graph of Concentration vs. time yields:
Cpmax 4.63 ng/mL
T max 1.7 hr
AUC (trap)30.07
K 0.225 hr^-1

Oral Dosing
m (-K) -0.225 hr^-1
Ka 1.22 hr^-1
f (AUCoral/Doseoral)/(AUCiv/Doseiv) = .98
Evaluation of the graph of response vs ln(concentration) yields:
dR/dln(c) = 27.86
Multiplying dR/dln(c) * dln(c)/dt (m of the previous graph) yields dR/dt = 27.86 *

-0.225 = 6.26%/hr
100 mic dose IV yields Cp0 of (Cp0 =AUC * K = 20.4 * 0.225) 4.59ng/mL.
The response of a 100 mic dose is (R = 27.86*ln(4.59)+19.9) 62.3%
Response = Response at t=0 - dR/dt * t
20% = 62.3% - 6.26%/hr * t hours
T = 6.76 hours
5. The following data was collected from a double blind cross over study between
500 mg dose of cloxacillin made by Bristol (Tegopen@) and a generic product
which you might want to put in your store.
Time (Conc. mic/ml) Time (Conc. mic/ml)
TEGOPEN GENERIC TEGOPEN GENERIC

Oral Dosing
0.25 .41 0.1 1.5 6.93 7.75
0.5 8.56 6.39 2 4.95 5.16
0.75 11.97 11.44 3 2.19 2.29
1 11.28 11.42 4 1.48 1.30
1.25 9.57 9.64
Calculate the comparative bioavailability.
Would you consider these products bioequivalent? Why/Why not?
Answer:

Oral Dosing
Evaluation of the above graphs yields:
Tegopen GenericRatio (G/T)
Cpmax (mic/mL)10.8 9.94 0.92
T max (hr) 0.74 0.89 1.20
AUC (trap) 21.7 21.06 0.97
K (hr^-1) 0.72 0.8
ka (hr^-1) 4.3 2.69
Actual evaluation of ka and peak time is dificult because of the pucity of data at
early time points however all relavent parameters meet guidlines.
7. The F.D.A. reported the following data submitted to be consideration regarding

the equivalence of Mylan Pharmaceuticals' Tetracycline with that of Lederle and
an intervenous bolus dose. (Dose 250 mg).
Time(hrs) Conc.(mcg/ml) Time(hrs) Conc.(mcg/ml)
Lederle Mylan I.V. Lederle Mylan I.V.
0.5 0.55 0.20 5.2 4 2.70 2.60 2.9
1 1.80 1.35 4.8 6 2.20 1.80 2.1
1.5 2.11 1.75 4.4 9 1.35 1.25 1.26
2 2.35 2.10 4.0 12 0.83 0.74 0.76

Oral Dosing
3 2.65 2.25 3.4 15 0.50 0.45 0.46
Would you consider Mylan to be bioequivalent to the Lederle product ?
Calculate the absolute bioavailability of Lederle Tetracycline.(.77)
f) Calculate the volume of distribution of tetracycline. (44.3 L)
g) Tetracycline has a pKa of 9.7. Tetracyclines tend to localize in the dentin and
enamel of developing teeth causing hypoplasia and permanent discoloration of
teeth. Would you recomend tetracyline for a 110 pound lactating mother ?
Support your argument with the dose of the child. (Child's weight 11 lbs. and he
eats 2 oz of milk every 2 hours. Mom's average plasma concentration is main-
tained at 3 mic/ml by taking 250 qid. pH of the milk is 6.1, pH of blood is 7.4)
Answer:

Oral Dosing
Pharmacokinetic parameters:
Lederle Mylan IV
Cpmax (mic/mL)2.75 2.42 5.65
Tmax (hr) 3.04 3.08 0
AUC 26.4 23.3 31.4
k (hr^-1) 0.165 0.161 0.167
Ka (hr^-1) 0.684 0.729
Ratio of bioequivalence parameters (Cpmax, Tmax and AUC) are all within guide-
lines. So, the would be considered bioequivalent.
Absolute bioavailability f (= (AUCoral/DOSEoral)/(AUCiv/DOSEiv) = (26.4/

250)/(31.4/250) is 0.84.

Oral Dosing
Volume of Distribution (Dose/Cp0 = 250 mg/ 5.65 mg/mL) is 44.2 L
The ratio of milk to blood is about 200.
r(m/b) = (10^(pKa-pH) + 1)milk / (10^(pKa-pH) + 1)blood
= (10^(9.7-6.1)+1)/(10^(7.4-6.1)+1) = 10^3.6/10^1.3 = 10^2.3 = 200
Dose the kid gets is mom's plasma concentration * Ratio(M/b) * volume of milk /
day = 3 mic/mL * 200 * 60cc * 12 feedings = 432 mg.day
Mom gets 1000 mg/day
Ratio of dose on a mg/kg basis (kid/mom) = (432/5)/1000/50) = 4.32 - Kid's get-

ting more than mom.
Fifty miligrams of ketameperidine was given by IV bolus. The following urinary

profile was obtained for the only metabolite N-methyl-ketameperidine:
Collection period (hr) Mean urinary excretion rate (mg/hr)
0.0 - 0.5 2.26
0.5 - 1.5 5.83
1.5 - 2.5 5.43
2.5 - 3.5 4.60
3.5 - 5.0 2.36

Oral Dosing
5.0 - 7.0 1.47
7.0 -10.0 0.96
10.0 -18.0 0.44
Calculate K, km and ku.
What Percent of ketameperidine was metabolized?
Answer:
With only one data point in the early time points, the larger rate constant is in ques-
tion. The terminal slope is assumed to be K. The AUC will yield the amount of
ketameperidine which was metabolized (dXmu/dt * t = Xmu).
K (hours^-1) 0.216
AUC (mg)30.3
30.3 mg showed up as metabolite = 60.6% of 50 mg dose.
km = 60.6% * K = 0.131 hours^-1

Oral Dosing
kr = K - km = 0.085 hours^-1
Aminophylline consists of THEOPHYLLINE (85% W/W) & Ethylene diamine

(15% W/W)
THEOPHYLLINE is the active compound measured in blood.
THEOPHYLLINE has a volume of distribution of 0.45 l/kg.
THEOPHYLLINE is 10% excreted unchanged and 90% metabolized to inactive

metabolites.
THEOPHYLLINE has a therapeutic range between 20 and 10 mg/l.
AUC FROM 0 to infinity for THEOPHYLLINE (given as 400 mg AMINPHYL-

LINE) is 120 mg/l x hr.
The average plasma concentration of THEOPHYLLINE given as 400 mg of AMI-

NOPHYLLINE is as follows:
time conc. time conc.
(hrs) (mg/L) (hrs) (mg/L)
0.5 7.24 4.0 8.06
1.0 9.56 6.0 6.89
2.0 10.00 8.0 5.57
3.0 8.84 10.0 4.53
Find f, K, ka, Vd,total body clearance.
Find the infusion rate necessary to maintain a plasma concentration of 15 mg/l.

Oral Dosing
Answer:
AUC (mg/L)*hr117.8
K (hr^-1) 0.096
ka (hr^-1) 2.11
f = (AUCoral/DOSEoral)/(AUCiv/DOSEiv) =
= (117.8 / 400 )/(120 / 400 ) = 0.98
Vd
AUC * K = Cp0iv
120 * 0.096 = 11.52 mg/L
Vd = Dose/Cp0 = (400mg*0.85)/11.52 = 29.5 L
TBC = K * Vd = 0.096/hr * 26.5L = 2.83 L/hr

Oral Dosing
Infusion rate = Q = Cpss * TBC = 15 mg/L * 2.83 L/hr = 42.45 mg/hr Theophyl-
line = 42.45/.85 = 50 mg/hr Aminophylline
Abbott labs has provided the following data conserning their ORETIC tablets
(hydrochlorthiazide tablets U.S.P.) Dose given was 50 mg.
time conc. time conc.
(hrs) (mg/L) (hrs) (mg/L)
0.5 0.05 3.0 0.31
1.0 0.21 4.5 0.23
1.5 0.27 6.0 0.18
2.0 0.31 8.0 0.12
a Find K, ka, Cmax,
Answer:

Oral Dosing
The data is plotted both without (first figure) and with (second figure) a lag-time
which is associated with the release of the drug from the delivery system. Note
that the addition of the lag-time improves the fit.
The parameters obtained from each fit are:
WithoutWith
Cpmax (mg/L)0.22 0.31
Tmax (hr) 3.45 2.28
AUC (mg/L*hr)2.2 2.26
K (hr^-1) 0.216 0.201
ka (hr^-1) 0.380 1.10
t lag (hr) 0.0 0.393

Oral Dosing
It takes the tablet about 20 minutes to release the drug!
Wilkenstein et al.(Gastroenterology 74:360,1978) tested 12 normal healthy volun-

teers in a four way crossover design of four dosage forms containing 300 mg of
cimetadine. The following data was obtained: A B C D
AUC(mic/ml x hr) --- --- 5.2 5.4
recovered in urine intact77.177.1 54.9 55.8
Peak serum conc.(mic/ml)--- --- 1.53 1.44
Onset (hr) 0 0.34 0.65
Duration (hr) 4.5 4.6 4.2 4.4
Time to peak (hr) 0 1.0 2.0
A = IV Bolus B=IM injection C = Oral liquid D= Oral tablet
The plasma concentration vs. time profile for product A is as follows:
time (hrs) conc.(ug/ml)
1 1.79
2 1.36
4 0.78
6 0.45
12 0.08
a} find K, Cp0.
Both can be found from the graph. K = .283/hr Cp0 = 2.36 mic/ml

Oral Dosing
5.2/8.5 = 0.61
Very well. Only 61% (f) of liquid gets in and you would expect only 77% of that
to show up in the urine because only 77% of the IV dose shows up in the urine
(0.61 * .77 = .47).
d} How can you explain the variation in % recovered intact in the urine?
e} Would you consider the oral forms bioequivalent ? Why/Why not?
No. The ratio of peak times is outside the guidelines.
f} What infusion rate would you suggest to maintain a plasma concentration of

0.75 mic/ml?
Q = Cpss * K * V = 0.75 mg/L * 0.283/hr * 125L = 26.54 mg/hr
g} How long would it take that infusion rate to attain a therapeutic plasma concen-
tration of 0.5 mic/ml ?
Cp = Q/(K * V)(1-exp(-K*T) = 0.5 = 26.54/(0.283 *125)*(1-exp(-0.283 * T)) -

> 3.9 hr
Roxane labs of Columbus, Ohio offers the following data for your review of their
Quinidine Sulfate tablets (Dose 200 mg). It is compared against the reference
standard by Ely Lilly and company at the same dose.

Oral Dosing
Time (hours)Concentration (mcg/ml)
Roxane Lilly
1 .42 .58
2 .73 .77
3 .71 .74
4 .61 .66
6 .45 .52
8 .32 .34
12 .20 .22
a) Calculate the comparative bioavailability.
b) Would you consider Roxane Quinidine Sulfate to be bioequivalent to the Lilly

product ?
Answers

Oral Dosing

Oral Dosing
Roxane labsEli Lilly
w/o w w/o w Rw/o(R/L)Rw(R/L)
Cpmax (mcg/mL)0.650.740.740.76 0.88 0.97
AUC (mcg/mL*hr)6.086.236.756.84 0.90 0.91
Tmax (hr) 2.69 2.05 2.33 2.10 1.15 0.98
T lag (hr) 0.0 0.70 0.0 0.36
Yes. Ratios are within guidelines.
Shand et al. offers the following data for propranolol : Answers:
Time Concentration (ng/ml)
(hours) 10 mg I.V. 80 mg oral
0.5 -- 50
1 -- 77
1.5 -- 100
2 29 100
3 24 90
4 18 78
5 15 59
6 11 45
7 9 32

Oral Dosing
a) find ka
b) Calculate the absolute bioavailability of propranolol.
c) Calculate TBC

Oral Dosing
IV data Oral Data
w/o w
AUC (ng/mL*hr)201.3562.8 540
Cpmax (ng/mL) 47.7 97.8 99.7
Tmax (hr) 0 2.0 2.1
K (hr^-1) 0.239 0.324 0.421
ka (hr^-1) --- 0.715 0.548
T lag 0.0 0.02
Absolute bioabailability = (AUCoral/DOSEoral)/(AUCiv/DOSEiv)
= (562.8/80) /(201.3/10) = 0.35 or using lag time data
(540 / 80) /(210.3/10) = 0.335
TBC = Dose / AUC = 10,000 mic/ 201.3 mic/L*hr = 50 L/hr or
0.35*80,000mic /562.8 mic/L*hr = 50 L/hr
Niazi et al. offers the following data for meperadine :
Meperidine : is 95% metabolized
has an absolute bioavailability of 0.4
has a hepatic plasma extraction ratio of 0.6
has a volume of distribution of 100 L.
has a half life of 3.5 hours.

Oral Dosing
a) Calculate TBC
TBC = K * V = (0.198/hr)(100L) = 19.8 L/hr
b) Calculate the intrinsic hepatic plasma clearance of meperidine.
19.8 L/hr * .95 = 18.8 L/hr
c) Calculate the effect on total body clearance in a patient with viral hepititis (FI =
0.3).
Clh*/Clh = (.3)(1)/1 + .6(.3 - 1) = .3/.58 = .517
(.517)(18.8) = 9.72
TBC = 1 + 9.72 = 10.72
d) Calculate the effect on total body clearance in a patient with stenosis (FR = 0.3).
Clr*/Clr = (1)(.3)/.3 + .6(1 - .3) = .3/.72 = .417
TBC = 18.8 + .417 = 19.22
e) Comment on which patient might need modification in therapy and why.
The patient with viral hepatitis would need modification in therapy. Because
of the decrease in TBC, we can see that the drug is staying the body much
longer than normal, therefore the dosage regimen should be decreased.
Chlorthalidone is used to treat high blood pressure. The following information is

offered regarding a generic
and a brand name chlorthalidone 50 mg tablet:
Time Conc. (mcg/ml)

Oral Dosing
(hours) Hygroton@Generic
.5 0.14 0.15
1 0.51 0.64
2 1.23 1.67
3 1.94 2.48
4 2.20 2.91
6 2.64 3.49
8 2.86 3.52
12 3.43 3.82
24 3.22 3.38
48 2.45 2.74
72 1.53 1.91
96 1.20 1.40
120 0.76 0.77
Pharmacokinetic parameters
Cpmax (mg) 3.73 4.62
Time to peak (hr) 13.810.8
AUC (0 to Inf)293 336
Xu inf (mg)18.3 22.1
Ka (hr^-1)0.168 0.253
Ke (hr^-1)0.019 0.019

Oral Dosing
Average mean83.1 84.5
blood presure
a) Calculate the comparative bioavailability.
(336/50mg)/(293/50mg) = 1.15
b) Would you consider the generic product to be bioequivalent to the USV

(Hygroton@) product? Prepare a short statement that you would tell a patient
regarding why you would or would not make a generic substitution for this drug.
No. The maximum concentration the generic is too much greater than that of
the brand name product.
They are not considered to be bioequivalent.
R(G/H)
Cpmax (mg) 1.23 outside
Time to peak (hr)0.78outside
AUC (0 to inf)115 ok
Buspirone is a new anxiolytic agent that has been found to be effective for the
treatment of generalized anxiety disorder at a mean dose of approximately 20 mg/
day orally in divided doses. Buspirone is metabolized almost entirely. Less than
0.1% is found intact in the urine. The following data has been presented by Gam-
mans (Am J Med:80(supp 3b),41-51;1986):
Time (hours)Concentration (ng/ml)
(hours) 1 mg I.V.20 mg oral

Oral Dosing
0.25 -- 1.07
0.50 4.33 1.76
1.0 3.75 2.45
2 2.80 2.51
3 2.10 2.05
4 1.57 1.60
6 0.8 0.91
a) find ka
b) Find Oral Peak Time and Oral Cmax.
c) Calculate the absolute bioavailability of buspirone.
answer:

Oral Dosing
IV Oral
Cpmax (ng/mL) 5.0 2.6
AUC (0 to inf)17.4 13.9
Tmax (hr) 0 1.5
K (hr^-1) 0.290 0.289
ka (hr^-1) 1.3
Absolute bioavailability, f, = (AUCoral/DOSEoral)/(AUCiv/DOSEiv)
= ( 13.9 / 20) /( 17.4/ 1 )
= 0.04
Valproate is a carboxylic acid anticonvulsant. Its activity may be related, at least

in part, to increase concentrations of the neurotransmitter inhibitor gamma ami-
nobutyric acid in the brain. It is used alone or in combination with other anticon-
vulsants. in the prophylactic management of petit mal. It appears to be almost
entirely cleared by liver function with negligible amounts excreted into the urine
unchanged. It comes as soft gelatin capsules of 250 mg and enteric coated tablets
250 and 500 mg as well as oral syrup of 250 mg / 5 cc. Two different formula-
tions of Valproate (250 mg) were prepared by Abbott and compared. The data is as
follows:

Oral Dosing
Time(Hr.)Formulation BFormulation A
0.5 3.4 AUC = 287 mg/L * hr
1.0 6.0 Ka = 0.7 hr^-1
1.5 7.9 Ke = 0.065 hr^-1
2.0 9.3
2.5 10.3
3.0 10.9
4.0 11.6
6.0 11.4
8.0 10.5
12.0 8.3
18.0 5.7
24.0 3.8
1) find ka for formulation B.
2) Five hundred mg of valproate was administered by IV bolus. The AUC for that
route was 574 mg/L * hr. Calculate f for formulation A. Calculate Cp0 for the IV
dose.
3) Find Peak Time and Cmax for formulation A.
4) Calculate the comparative bioavailability of formulation B.
5) Would you consider formulation B to be bioequivalent to Formulation A ? Pre-

pare a short statement in which you would substantiate that stand that you might

Oral Dosing
need to respond to another health professional who asked you to stock that formu-
lation for his patients.
6) Calculate the Total Body Clearance (TBC) of valproate.
Answers:
Formulation B R(A/B)
AUC = 243.3 mg/L * hr 1.18
Cpmax = 11.7 mg/L1.12
Tp max = 4.70 hr0.79
ka = 0.493 hr^-1
K = 0.0655
Tmax(A) = ln(ka/K)/(ka-K)= 3.75 hr
cpmax =
(ka/(ka-k))*(fX0/Vd)*(exp(-k*tmax)-exp(-ka*tmax)
13.3 mg/L
Absolute bioavailability, f,=(AUCoral/DOSEoral)/(AUCiv/DOSEiv)
= (287/250)/(574/500)
= 1.0

Oral Dosing
Comparative bioavailability =(AUCb/DOSEb)/(AUCa/DOSEa) = 243.3/287 =

0.85
TBC = Dose / AUC = 500 mg / 574 mg /L * hr
The following data was made available by Lederle Labs regarding its generic
Procainamide HCl. (Dose 250mg).
Procainamide is a base (pka =9.1). As the hydrochloride salt it is 87% Procaina-

mide.
Time (hrs)Conc.(mcg/ml) Procainamide Base
Lederle Squibb I.V.
0.33 0.68 0.26
0.5 0.82 0.67
0.66 1.17 0.93
1 1.23 1.12 1.45
1.33 1.31 1.19 1.35
2 1.39 1.12 1.18
3 0.93 0.96 0.95
4 0.74 0.74 0.77
6 0.51 0.51 0.51
8 0.32 0.30 0.33
12 0.11 0.09 0.14

Oral Dosing
a) find ka of the Squibb product
b) ka of the Lederle product.
c) Calculate the comparative bioavailability.
d) Would you consider Lederle to be bioequivalent to the Squibb product ?
e) Calculate the absolute bioavailability of Lederle Procainamide.
f) Calculate the volume of distribution of procainamide.
g) Would you recommend your patient breast feed her newborn? Prepare a short
consult for her physician. Support your argument with the dose of the child.
(Child's weight 11 lbs. and he eats 2 oz of milk every 2 hours. Mom's average
plasma concentration is maintained at 4 mic/ml from a 1 g dose ever 6 hours. pH of
the milk is 6.3, pH of blood is 7.4)
Procainamide is cleared about 60% by liver and 40% by kidney function. 20 % of

cardiac output (70 ml/min/kg) goes to liver, 25% goes to the kidney. Mom's
weight is 130 lb. Assuming her plasma vs time profile to be similar to the Lederle
product (i.e. pharmacokinetic parameters obtained from this information can be
used):
h) Calculate Total body clearance
i) Calculate the intrinsic hepatic plasma clearance of procainamide.
j) Calculate the effect on her total body clearance if she were to contract viral hep-
atitis which effect liver function (FI = 0.4). Prepare a short consult for her physi-
cian as to whether you would recommend a change in therapy. d) Calculate the
effect on her total body clearance stenosis of the liver (FR = 0.4). Prepare a short
consult for her physician as to whether you would recommend a change in therapy.
Answers:

Oral Dosing
IV LederleSquibb R(L/S)
AUC (0 to inf)8.577.46.8 1.09
Cpmax 1.8 1.28 1.25 1.02
Tmax 0 1.43 1.45 0.99
K 0.212 0.247 0.256
ka --- 1.51 1.93
t lag 0 0 0.24
= 7.4 / 8.57

Oral Dosing
= 0.86
Vd = Dose/Cp0 = 0.87*250mg/1.8mg/L= 120.8 L
Ratio of milk to blood = (10^(9.1-6.3)+1)/(10^(9.1-7.4)+1)= 12.4
Kid's dose = 4 mic/mL * 12.4 * 60 mL/feeding * 12 feedings/day * 1 mg/1000 mic

= 36 mg/day
Ratio of kid's daily dose/# to Mother's daily dose/# = (36mg/11#)/(1000mg*4/

130#) = 0.42. The kid gets about half of the mother's dose!
Nifedipine (Procardia @) is a calcium channel blocker which specifically inhibits

potential-dependent channels not receptor-operated channels, preventing calcium
influx of cardiac and vascular smooth muscle (coronary, cerebral). Calcium
channel blockers reduce myocardial contractility and A-V node conduction by
reducing the slow inward calcium current. They are indicated in angina, cardiac
dysrhythmias, and hypertension among others. Nifedipine appears to be metabo-
lized entirely into an inactive metabolite, an acid and subsequently further metab-
olized to a lactone. Both the acid and the lactone are excreted into the urine and
the feces.
Echizen and Eichelbaum (Clin Pkin 1986; 11:425-49) and Kleinbloesem et al (Clin
Pcol Therap 1986; 40: 21-8) Reviewed the pharmacokinetics of Nifedipine. While
the drug is not routinely given by IV bolus and does not strictly conform to a one
compartment model, lets treat the data as if those problems can be ignored. The
following data is offered for evaluation:
25mg IV 10 mg oral tablet
Formula AFormula B
Time Cp Cp Cp

Oral Dosing
(hr.) (mic/l) (mic/l) (mic/l)
0.5 29.3 33.1
1 42.1 43.7
1.5 45.7 43.7
2 139 44.4 39.8
3 36.2 25.5
4 65.6 27 20.7
6 31.1 13.6 9.9
8 14.6 6.5 4.7
12 1.5 1.0
a} Find ka's of the two products.
b} Calculate peak time and Cp max for both products.
d} Can you conclude that these products are bioequivalent ? (you must support you
argument)
e) Calculate the absolute bioavailability of product A.
f} What infusion rate would you suggest to maintain a plasma concentration of 30

mic/L ?
Answers:

Oral Dosing
IV A B R(A/B)
Cpmax (mic/L)294.25 45.7 44.01.04
Tmax (hr) 0 1.57 1.18 1.33
AUC(0 to inf)785219.7182.7 1.20
ka (hr^-1)--- 1.0 1.6
K (hr^-1) 0.375 0.374 0.375
No,Tmax is outside the guidelines.

Oral Dosing
=(219.7/10)/(785/25)
=0.7
Q = Cpss * K * V = 0.955 mg/hr
Tetracycline HCl has a pKa of 9.7. Tetracyclines tend to localize in the dentin and
enamel of developing teeth causing hypoplasia and permanent discoloration of
teeth. Would you recommend tetracycline for a lactating mother ? Support your
argument with the dose of the child. (Child's weight 11 lbs. and he eats 2 oz of
milk every 2 hours. Mom's average plasma concentration is maintained at 4 mic/
ml she is taking 250 mg T.I.D. ( Milk pH = 6.1, Blood pH = 7.4)
Tm/Tb = 109.7 - 6.1/109.7 - 7.4 = 20/1
The concentrarion of tetracycline in the mother's milk is 80 mic/ml
The child takes in 720 ml of milk per day
80 mic/ml * 720 ml = 57600 mic = 57.6 mg
57.6mg/5kg = 11.52mg/kg = dose that the child is getting from the mother's
milk.
I would not recomend tetracycline for a lactating mother. The dose that a nurs-
ing child gets from the milk too high.
Oxazepam (acid, pKa 11.5) is an anxyolytic sedative with the usual adult dose 10
mg 3 times daily. If the circulating plasma concentration of oxazapam were 20

Oral Dosing
mic/ml for nursing 120 lb mother, would her 9 lb infant be getting a comparable
mg per kg daily dose if he consumes 2 oz of his mothers milk every 2 hours. Pre-
pare a short consult for her physician in which you might (or might not) recom-
mend the patient stop breast feeding while she is on this medication. Include
appropriate calculations.
Om/Ob = 1011.5 - 6.1/1011.5 - 7.4 = 20/1
The concentration of the mother's milk would then be 400 mic/ml
400 mic/ml * 720 ml = 288000 mic given to baby = 288mg
288mg / 4.1kg = 70 mg/kg = dose/kg given to baby
This dose is much greater then that given to the mother. The mother should
discontinue breast feeding while taking Oxazepam.
Bioequivalence studies are sometimes done within the same company to check if
the tablets of the same drug, but different strengths (with the strength normalized)
could be considered equivalent (i.e. could two 5 mg tablets be considered equal to
one 10 mg tablet). While not strictly kosher (products are not pharmaceutical
equivalents because of different strengths), it is done. Here is the results of such a
study in which Zomax 100 and 200 mg tablets were compared. (Yes, I know that
Zomax was removed from the market after a short life of only 6 months.)
Zomax 100 mg tablet 200 mg tablet 50 mg IV bolus
Time Conc AUC Conc AUC Conc.
(hr) (mg/L) (0->t) (mg/L) (0->t) (mg/L)
0.25 1.41 0.18 4.03 0.50
0.5 1.98 0.60 5.13 1.65
0.75 2.15 1.12 5.18 2.94
1 2.12 1.65 4.89 4.20 1.14

Oral Dosing
2 1.56 3.49 3.37 8.33 0.764
3 1.05 4.80 2.26 11.14 0.512
4 0.707 5.67 1.51 13.03 0.343
6 0.318 6.70 0.68 15.22 0.154
8 0.143 7.16 0.306 16.20 0.069
1) What is the elimination rate constant for zomax (hr) ?
A) 0.2 B) 0.3 *C) 0.4 D) 0.5 E) 0.6
2) What is the volume of distribution of zomax given by IV bolus (L) ?
A) 43.85 B) 33.3 *C) 29.4 D) 25.9 E) 0.034
AUC = D/(Vd * K)
Vd = D/(AUC * K)
= 50mg/(4.25 * 0.4)
= 29.4 L
3) What is the volume of distribution of zomax given by 100 mg oral tablet ?
A) 43.85 *B) 33.3 C) 29.4 D) 25.9 E) 0.034
Vd = 100mg/(7.48 * 0.4)
= 33.4 L

Oral Dosing
4) What is the AUC(0->infinity_ for the IV bolus dose ?
A) 2.68 B) 2.85 C) 3.55 D) 4.08 *E) 4.25
5) What is the AUC(0->infinity) for the 100 mg tablet ?
A) 7.16 *B) 7.5 C) 16.20 D) 17 E) 37.38
6) What is the absolute bioavailability of the 100 mg tablet ?
A) 0.84 *B) 0.88 C) 1 D) 1.14 E) 1.19
(7.48/100)/(4.25/50) = 0.88
7) What is the AUC(0->infinity) for the 200 mg tablet ?
A) 7.16 B) 7.5 C) 16.20 *D) 17 E) 73.98
8) What is the absolute bioavailability of the 200 mg tablet ?
A) 0.84 B) 0.88 *C) 1 D) 1.14 E) 1.19
(16.9/200)/(4.25/50) = 1
9) What is K * AUC (0->infinity) for the 100 mg tablet (mic/ml) ?
A) 2.9 *B) 3.0 C) 6.5 D) 6.8 E) 14.95
7.48 * 0.4 = 2.99

Oral Dosing
10) What is the absorption rate constant for the 100 mg tablet ?
A) 1.7 B) 2.2 *C) 2.6 D) 3.2 E) 3.7
11) What is the intercept of the extrapolated line for the 200 mg tablet ?
A) 3.5 B) 4.1 C) 5.6 D) 6.1 *E) 7.6
12) What is the absorption rate constant for the 200 mg tablet ?
A) 1.7 B) 2.2 C) 2.6 D) 3.2 *E) 4.01
13) What is the Tmax for the 100 mg tablet ?
A) 0.5 B) 0.67 C) 0.75 *D) 0.85 E) 0.95
14) What is the Tmax for the 200 mg tablet ?
A) 0.5 *B) 0.67 C) 0.75 D) 0.85 E) 0.95
15) Would you consider these two tablets bioequivalent (given normalization for
dose) (consider all ratios to be the 100 mg / 200 mg parameter normalized as to
dose where applicable)?
A) Yes
B) No, because the ratio of the ka's is 0.70
C) No, because the ratio of the AUCs is 0.44

Oral Dosing
D) No, because the ratio of the Cmaxs is 0.41
*E) No, because the ratio of the Tmaxs is 1.27
16) What infusion rate would you recommend to maintain an average plasma con-
centration of 1 mic/ml ?
A) 17.5 B) 13.3 *C) 11.8 D) 10.4 E) 9.0
Vd = D/Cp0 = 50mg/1.7mg/L = 29.4
Q = Cpss * K * V = 1mg/L * 0.4/hr * 29.4L = 11.8
17) What would be the concentration (mg/L) 2 hrs after discontinuing the infu-
sion assuming you reached steady state ?
A) 0.67 B) 0.55 *C) 0.45 D) 0.37 E) 0.30
Cpss = Cp0 * e-Kt
= 1mg/L * e(-0.4 * 2)
= 0.44
A 110 pound mother breast feeds her 11 pound infant while on morphine sulfate
(base, pKa = 9.85). Mother's average circulating plasma levels are 0.5 ug/ml fol-
lowing a 10 mg IV dose q4h. (pH Milk = 6.1, pH blood = 7.4)
18) What is the Ratio of morphine concentration in the milk as compared to the
blood ?
A) 0.05 B) 0.5 C) 1 D) 2 *E) 20

Oral Dosing
Mm/Mb = 10(9.85 - 6.1)/10(9.85 - 7.4)
= 20
19) How much (mg) morphine is contained in 120 cc of breast milk (the child con-
sumes 2 ounces every 2 hours) *A) 1.2 B) 0.12 C) 0.06 D) 0.03 E) 0.003
Mother's blood conc. is 0.5mic/ml therefore her milk conc. is 10 mic/ml.
10mg/L * 0.12L = 1.2 mg
20) In your professional judgment, will the child's dose cause a problem ?
A) No, morphine does not concentrate in the milk and thus the milk is ok to drink.
B) No, the dose is too small. The ratio of the child's dose to the mother's dose is
0.12.
C) Yes, even though the dose is small, we don't want any drug to get to the child.
*D) Yes, the dose is comparable to the mother's dose. The ratio of the child's to the
mother's dose is 1.2.
E) Not my job. I only give what the doctor orders.
Answers:

Oral Dosing
IV Tablet Tablet
50 mg 100 mg200 mgR(100/200)
AUC(0 to inf)4.257.4816.9 0.89
Cpmax 1.7 2.15 5.23 0.82
Tmax 0 0.82 0.64 1.28
K 0.4 0.4 -.4
ka --- 2.76 4.01
Tmax ratio is ouside guidelines.

Oral Dosing
Answers are rounded off. When you pick a foil, use that number in subsequent cal-
culations when needed.
Rifampin (unionized free base pKa 7.9) is a drug used to treat TB. The following
data was collected following a 600 mg oral tablet from the inovator (Treatment A),
and a 600 mg oral tablet from a generic (treatment B), and a 400 mg IV dose
(Treatment C).
Concentration (mic/mL)AUC(0->t)
TreatmentA B C B
Time (hours)
0.5 5.3 4.8 1.2
1 10.3 8.6 7.8 4.55
1.5 10.2 9.8 9.15
2 9.4 9.8 6.1 14.05
2.5 8.9 9.2 18.8
3 7.5 8.4 4.7
4 5.9 6.7 3.7
6 3.6 4.1 2.2
8 2.2 2.5 1.3
10 1.3 1.5 0.8
12 0.8 0.92 0.5
AUC(0->inf)53.957.7

Oral Dosing
(mic/mL*hr)
Lag time (min)18.610.5
Cp max10.6 9.9
Ka (hr^-1)2.66
1) What is the Cp0 for C (mg/L)? a) 0 b) 7.8 *c) 10 d) 12 e) 15
Cp0 = AUC * K
= 39.8 * 0.25
= 9.95
2) What is the volume of distribution of Rifampin (L)? a) 60 b) 51.3 *c) 40

d) 33.3 e) 26.7
Vd = D/Cp0
= 400mg/(9.95mg/L)
= 40.2 L
3) What is the half life for rifampin (hr)? *a) 2.8 b) 2.3 c) 2.0 d) 1.75 e)
1.5
t1/2 = .693/0.25
= 2.77

Oral Dosing
4) What is the elimination rate constant for rifampin (hr^-1)? *a) 0.25 b) 0.3 c)
0.35 d) 0.4 e) 0.45
5) Calculate the AUC (0->1hr) for C (mic/mL*hr). a) 1.95 *b) 3.9 c) 7.8 b)
8.9 e) 17.8
6) Calculate the AUC (12hr->inf.) for C (mic/mL*hr). *a) 2 b) 1.67 c) 1.43

d) 1.25 e) 1.11
0.5/0.25 = 2
7) Calculate the AUC (0->inf) for C (mic/mL*hr). a) 16 b) 26.85 c) 35 *d)

40 e) 60
8) Calculate the absolute bioavailability for the generic product. a) 0.70 *b)
0.95 c) 1 d) 1.05 e) 1.43
(57.7/600)/(39.8/400) = 0.966
9) Calulate the comparative bioavailability for the generic product. a) 0.70 b)

0.95 c) 1 *d) 1.05
e) 1.43
(57.7/600)/(53.9/600) = 1.07
10) Using Wagner-Nelson method, calculate the Ka for the generic product (hr^-
1). a) 0.45 b) 1 c) 1.55 d) 2 e) 2.45

Oral Dosing
11) Calculate the peak time for the generic product (min). a) 37 b) 67 c) 86 d)
91 e) 105
tp = [ln(Ka/K)]/(Ka - K)
= [ln(1.37/0.25)]/(1.37 - 0.25)
= 1.52 hr = 91 min
12) Calculate the peak time for the brand name product (min). a) 37 *b) 59 c)
86 d) 95 e) 105
tp = [ln(2.66/0.25)]/(2.66 - 0.25)
= 0.98 hr = 59 min
13) Are the two products bioequivalent?
a) yes, all federal requirements are met.
*b) no, the ratio of the peak times are out side federal requirements.
c) no, the ratio of the lag times are out side federal requirements.
d) no, the ratio of the Kas are out side federal requirements.
e) no, the ratio of the comparative bioavailabilities are out side federal require-
ments.
14) What is the ratio of the concentration of milk (pH 6.1) to blood (pH 7.4)? a)
0.05 b) 0.05 c) 1 d) 15.4 *e) 20
Rm/Rm = 10(7.9 - 6.1)/10(7.9 - 7.4)

Oral Dosing
= 20
15) The average plasma concentration for the mother (110#) is 2.5 mg/L from a
600 mg once a day dosing regimen. If the baby (11#) drinks 780 mL of milk a day
(2 - 2.5 ounces every 2 hours), what is his daily dose (mg)?
a) 0.1 b) 0.13 c) 2 d) 30 *e) 39
Mother's blood average blood conc. is 2.5 mg/L therefore her milk conc. is 50
mg/L.
If the baby drinks 780 ml of milk he/she will get 39 mg of the drug.
16) Would you recommend mom stop breast feeding? (What % of the mom's daily
dose (mg/kg) is the baby's daily dose (mg/kg)?)
a) No, the child's dose is less than 1% of the mother's dose on a mg/kg/day basis.
b) No, the child's dose is about 5% of the mother's dose on a mg/kg/day basis.
c) Maybe, the child's dose is about 10% of the mother's dose on a mg/kg/day basis.
*d) Yes, the child's dose is about 50% of the mother's dose on a mg/kg/day basis.
e) Yes, the child's dose is about the same as the mother's dose on a mg/kg/day
basis.
17) While Rifampin is not administered by IV infusion, what would be the infu-
sion rate necessary to maintain an average plasma concentration of 2.5 mg/L (mg/
hr)? *a) 25 b) 50 c) 100 d) 150 e) 200
Vd = D/Cp0
= 400/10.02
= 39.9 L

Oral Dosing
Q = Cpss * K * Vd
= 2.5 * 0.25 * 39.9
= 25 mg/hr
18) While Rifampin is not administered by IV bolus, what would be the loading
dose necessary to obtain a plasma concentration of 2.5 mg/L (mg)? a) 25 b) 50
*c) 100 d) 150 e) 200
Loading Dose = Cpss * Vd
= 2.5 * 39.9
= 100mg
19) While Rifampin is not administered by IV infusion, what would be the infu-
sion rate necessary to obtain a plasma concentration of 2.5 mg/L in about 2.5 to 3
hours (mg/hr)? a) 25 *b) 50 c) 100 d) 150 e) 200
Cp = [Q/(K * Vd)] * (1 - e-kt)
Q = (Cp * K * Vd)/(1 - e-kt)
= (2.5mg/L * 0.25 * 39.9L)/[1 - e(-0.25 * 2.75)]
= 50 mg/hr
20) Rifampin is a semisynthetic derivative of rifamycin B, an antibiotic derived

from Streptomyces mediterranei. The minimum inhibitory concentration for N.
menengitidis is 0.1 - 1 mic/mL. It is distributed well into bodily fluids. About 30%
shows up in the urine as free drug and active metabolite while 60% shows up in the
feces as metabolite. The secretary is hounding me to finish the exam, so the
answer to 20 is a. Also, rifampin is 85% protien bound at physiological concen-
trations. *a) 25 b) 50 c) 100 d) 150 e) 200
Answers:

Oral Dosing
A B IV
Tmax 1.27 1.7 0
K 0.25 0.25 0.25
ka 2.66 1.37 ---
AUC 53.9 57.7 39.8

Oral Dosing
Cpmax 10.6 9.9 10.02
PHARMACOKINETICS SECOND HOUR PRACTICE EXAM #2
(1) Succinctly define, stating rigorously the meaning of any symbols used and the
dimensions of measurement:
a}Cpss b}feathering c}Wagner-Nelson method d}clearance e}f
(2) For each of the following pairs of variables (ordinate against abscissa), draw
a graph illustrating the qualitative profile of their relationship. Where appropri-
ate, indicate the nature of important slopes, intercepts, and values. Unless your
specifically indicate on your plot that semi-log paper is being considered (write "S-
L"), it will be assumed that rectilinear paper is being considered. Graphs are for a
drug given by oral route where applicable.

Oral Dosing
a} total amount of drug collected minus the amount collected at the time in the
urine vs time
b} Plasma concentration of a drug given by oral route vs time
c} Plasma concentration of metabolite of a drug given by IV bolus vs time
d} Steady state plasma concentration vs infusion rate
e} Steaty state plasma consentration vs clearance
SECTION I
(1) Succinctly define, stating rigorously the meaning of any symbols used and the
dimensions of measurement:)
a}Cpss b}f c}Absolute Bioavailability d}Comparative Bioavailability
(2) Compare and contrast:a}Wagner-Nelson and feathering methods b} Treat-

ment of plasma and urine data using Wagner-Nelson
(3) For each of the following pairs of variables (ordinate against abscissa), draw
a graph illustrating the qualitative profile of their relationship. Where appropri-
ate, indicate the nature of important slopes, intercepts, and values. Unless your
specifically indicate on your plot that semi-log paper is being considered (write "S-
L"), it will be assumed that rectilinear paper is being considered. Graphs are for a
drug given by oral route where applicable.
dXu/dt vs t for a drug given orally.

Oral Dosing
dXmu/dt vs t for a drug given by IV bolus.
Steady state plasma concentration vs infusion rate
Steady state plasma concentration vs elimination rate constant
SECTION I
1. Succinctly define, stating rigorously the meaning of any symbols used and the
a) clearance b)f c) absolute bioavailability d) comparative bioavailability e)

AUC
2. By means of an annotated phase diagram explain how freeze-dried pharmaceuti-

cal injectables are made.
3. For each of the following pairs of variables (ordinate against abscissa) draw a
graph illustrating the qualitative profile of their relationship. Where appropriate,
indicate the nature of important slopes, intercepts, and values. Unless you specifi-
cally indicate on your plot that semi-log paper is being considered (write "SL"), it
will be assumed that rectilinear paper is being considered.
Pharmacological Response vs time
Peak time vs ka for oral dose
Fractional change in total body clearance vs. renal clearance

Oral Dosing
AUC vs ka
AUC vs ke
SECTION I
a) first pass effect b) f c) Intrinsic clearance
d) comparative bioavailability e) Extraction ratio
2. By means of an annotated phase diagram explain how a metastable polymorph

can be formed and how these polymorphs might effect the bioavailability of the
drug.
indicate the nature of important slopes, intercepts, and values. Unless your specif-
ically indicate on your plot that semi-log paper is being considered (write "S-L"),
it will be assumed that rectilinear paper is being considered
fractional change in total body clearance vs plasma flow for drugs having a large
extraction ratio.
Peak time vs ka for oral dose
Fractional change in total body clearance vs. hepatic clearance.
AUC vs ka

Oral Dosing
AUC vs clearance
SECTION I
Henderson-Hasselbach relationship
Therapeutic alternatives
Therapeutic equivalents
comparative bioavailability
Extraction ratio
Briefly discuss generic substitution by the pharmacist. Include such topics as when
it might be admissable and the liabilities involved.
indicate the nature of important slopes, intercepts, and values. Unless you specif-
a) fractional change in total body clearance vs fractional change in plasma

flow for drugs having a small extraction ratio.

Oral Dosing
b) Peak time vs dose for oral dose
c) Fractional change in total body clearance vs. fractional change in hepatic

clearance for drugs having a large extration ratio.
d) Ratio of milk to blood for basic drugs vs pKa.
e) Ratio of milk to blood for acidic drugs vs pKa.
SECTION I
a) Bioequivalance
b) Intrinsic Clearance
c) first pass effect
d) Henderson - Hasselbach equation
e) f
2.Compare and contrast absolute and relative bioavailability.
3.For each of the following pairs of variables (ordinate against abscissa) draw a
indicate the nature of important slopes, intercepts, and values. Unless you specif-

Oral Dosing
a) Cpmax vs f for a drug given orally.
b) Cpmax vs dose for a drug given orally.
c) Cpmax vs Vd for a drug given orally.
d) TBC vs Fi(H) for a drug with a high extraction ratio in the liver.
e) TBC vs Fr(H) for a drug with a high extraction ratio in the liver
SECTION I
a) Henderson-Hasselbach relationship
b) Therapeutic alternatives
c) Therapeutic equivalents
d) Comparative bioavailability
e) Extraction ratio
2. Briefly discuss generic substitution by the pharmacist. Include such topics as

when it might be admissible and the liabilities involved.
indicate the nature of important slopes, intercepts, and values. Unless you specifi-
cally indicate on your plot that semi-log paper is being considered (write "SL"), it
will be assumed that rectilinear paper is being considered
a) fractional change in total body clearance vs fractional change in plasma

flow for drugs having a small extraction ratio.

Oral Dosing
b) Peak time vs dose for oral dose.
c) Fractional change in total body clearance vs. fractional change in intrinsic

hepatic clearance for drugs having a large extraction ratio.
d) Ratio of blood to milk concentrations for basic drugs vs pKa.
e) Ratio of blood to milk concentrations for acidic drugs vs pKa.
PHARMACOKINETICS SECOND HOUR PRACTICE EXAM # 10
SECTION I
a) Henderson-Hasselbach relationship
b) Therapeutic alternatives
c) Therapeutic equivalents
d) Comparative bioavailability
e) Absolute bioavailability
f) Bioequivalents
2. Compare and Contrast: Feathering and Wagner-Nelson method.
3. For each of the following pairs of variables (ordinate against abscissa), draw a
indicate the nature of important slopes, intercepts, and values. Unless you indicate
on your plot that semi-log paper is being considered (write SL), it will be assumed
that rectilinear paper is being considered. Graphs are for a drug given by an oral
delivery system where applicable.
a) Cpss vs. K
b) Cp vs. ka

Oral Dosing
c) Ratio of Milk to Blood for acidic drugs vs. pKa
Pharmacokinetics practice exam #11
Pharmaceutical alternatives may have different:
I. therapeutic moieties
II. dosage forms or strengths
III. salt or ester forms of the same therapeutic moiety
2) Pharmaceutical equivalents must have the same:
I. active ingredients and strength
II. dosage form and route of administration
III. rate and extent of absorption
3) Bioequivalent drug products must have the same:
I. active ingredients and strength
II. dosage form and route of administration
III. rate and extent of absorption
4) Therapeutic equivalents are:

Oral Dosing
I. pharmaceutical alternatives
II. pharmaceutical equivalents
III. bioequivalents
5) The Wagner-Nelson method
I. uses curve stripping or feathering techniques
II. can be used to find ku and km
III. uses AUC calculations
6) The Federal guidelines for for bioequivalence require that the following phar-
macokinetic parameters be within + 20 % of
the innovator's product:
I. AUC, Peak time, Cpmax
II. Ka, Ke
III. Vd
7) The steady state plasma concentration of a drug given by intravenous infusion is

dependent on:
I. length of time of of infusion
II. volume of distribution
III. elimination rate constant, K.
8) The peak time of a drug given by the oral route is dependent on:

Oral Dosing
I. the absorption rate constant
II. the metabolism rate constant
III. the excretion rate constant
9) The slope of the terminal portion of the graph of the metabolite of a drug which
(the drug, not the metabolite) was given
by intravenous bolus injection could be:
I. - the elimination rate constant of the metabolite
II. - the elimination rate constant of the drug
III. - the absorption rate constant of the metabolite
10) Comparative bioavailability includes calculations of the ratio(s) of the fol-

lowing pharmacokinetic parameters of two
oral products (generic / Innovator) normalized for dose :
I. AUC (0 to Inf)
II. Peak time
III. Cpmax
Pharmacokinetics practice second hour exam #12

Oral Dosing
Where the are only three foils (possible quesses), please use K type system:
(NOTE: if foils are equivalent, all must be selected)
A) I ONLY
B) III ONLY
C) I AND II ONLY
D) II AND III ONLY
E) I, II, AND III
1) Steady state plasma concentration obtained by continuous infusion is inversely

proportional to:
I Infusion rate
II elimination rate constant
III volume of distribution
2) Steady state plasma concentration obtained by continuous infusion is directly

proportional to:
I Infusion rate
II time
III volume of distribution
3) When calculating the AUC for an oral product using the trapezoidal rule, con-
centrations necessary to calculate the
first trapezoid are:

Oral Dosing
I the intercept of the extrapolated line of the plasma vs. time profile.
II the concentration at time zero, Cp0
III the concentration at the first time point
4) When calculating the AUC for an IV product using the trapezoidal rule, con-
centrations necessary to calculate the
first trapezoid are:
I the intercept of the extrapolated line of the plasma vs. time profile.
II the concentration at time zero, Cp0
III the concentration at the first time point
5) Absolute bioavailability is a calculation which
I must be between .80 and 1.20
II compares an oral product to an IV bolus dose.
III is the ratio of the normalized AUCs of the products tested.
6) Comparative bioavailability is a calculation which
I is the ratio of the normalized AUCs of the products tested.
II must be between .80 and 1.20
III compares an oral product to an IV bolus dose.
7) When plotting the Wagner-Nelson function vs. time, a plot which proceeds hor-
izontally for a measurable time and then
declines:

Oral Dosing
I is because of poor data in the early part of the data set.
II only the declining portion should be used to calculate ka.
III is an indication of a delay in release of the drug from the delivery system, a lag
time.
8) When considering ion trapping, comparing a drug which forms sulfate salts
distributing between mother's milk and
blood, the ratio of total drug in milk to total drug in blood (Rm/b) can be
I greater than one.
II one.
III less than one.
9) When considering ion trapping, comparing a drug which forms sodium salts
distributing between mother's milk and
blood, the ratio of total drug in milk to total drug in blood (Rm/b) can be
I greater than one.
II one.
III less than one.
10) When using dry starch as a tablet disintegrating agent,
I tablet hardness is directly proportional to starch content.
II starch acts by allowing the water to wick into the tablet.
III a threshold minimum amount of starch is necessary before any disintegration

action is apparent.

Oral Dosing
Cyclosporine A (Problem 8 - 6)
Quigano, R., et al., "Effect of atropine of gastrointestinal motility and the bioavailability of cyclosporine A in rats", Drug Metabo-
lism and Disposition, Vol. 21, No. 1, (1993), p. 141 - 143.
In this study rats with an average weight of 300 g were given either an IV bolus dose of cyclosporine A (CyA)
or an oral dose of CyA. Subsequently, doses of atropine were given; however, the data below is that which was gath-
ered prior to atropine administration. A summary of the some of data obtained from this experiment is given below.
From the preceding data, please calculate the following:
Parameter IV Oral Solution Brand Tablet Generic Tablet Bioequivalence

Dose (mg/kg)
AUC  -------
ug- ⋅ hr
 mL 
AUMC  -------
ug- ⋅ hr 2
 mL 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  --------
ug
 mL
Vd (L)
Cp at 1 hour  -------
ug-
 mL
Cpmax  --------
ug
 mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
1. MRT iv
2. k e , the elimination rate constant
3. t1 ⁄ 2

Oral Dosing
4. Cp 0
5. Vd
6. The plasma concentration ( Cp ) of cyclosporine A at 1 hour after the iv dose was given.
7. AUC 0 – 1 hour for the iv dose
8. f , the absolute bioavailability of oral cyclosporine A.

9 MRT oral .
10. MAT oral
11. k a , the apparent absorption rate constant.
12. t peak for the oral dose.
13. Cp max , the maximum concentration of the oral dosage form given as a single dose.

Oral Dosing
Fosinopril (Problem 8 - 7)
Gehr, T., et al., "The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients", European Journal of Clin-
ical Pharmacology, Vol. 45, No. 5, (1993), p. 431 - 436.
Fosinopril (MW 562.6) is a new Angiotension Converting Enzyme (ACE) Inhibitor used in the treatment of
hypertension. Following oral administration, fosinopril is rapidly and almost completely hydrolyzed to its pharmaco-
logically active metabolite, fosinoprilate (MW 435.2). About 50% of the drug is excreted unchanged through the kid-
neys. In this study, patients received either 7.5 mg of fosinoprilat administered intravenously or 10 mg of fosinopril
administered orally. A summary of the some of data obtained from this experiment is given below.

Dose (mg/kg)
AUC  -------
ug- ⋅ hr
 mL 
AUMC  -------
ug- ⋅ hr 2
 mL 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  -------
ug-
 mL
Vd (L)
Cp at 1 hour  --------
ug
 mL
Cpmax  --------
ug
 mL
Tmax (hr)
1. MRT iv

Oral Dosing
3. t1 ⁄ 2
4. Cp 0
5. Vd
6. The plasma concentration ( Cp ) of fosinopril at 1 hour after the iv dose was given.
8. f , the absolute bioavailability of oral fosinopril.

9 MRT oral .
10. MAT oral

Oral Dosing
Verapamil (Problem 8 - 8)
Rutledge, D., Pieper, J., and Mirvis, D., "Effects of chronic phenobarbital on verapamil disposition in humans", The Journal of
Pharmacology and Experimental Therapeutics, Vol. 246, No. 1, (1988), p. 7 - 13.
This study focused on the effects of phenobarbital, a hepatic-enzyme inducer, on verapamil. Seven healthy
male volunteers with an average weight of 78.8 kg participated in the study. The patients received either an single oral
verapamil dose of 80 mg or a single intravenous verapamil dose of 0.15 mg/kg over 3 minutes. A summary of the some
of data obtained from this experiment is given below.

Dose (mg/kg)
AUC  -------
ug- ⋅ hr
 mL 
AUMC  -------
ug- ⋅ hr 2
 mL 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  --------
ug
 mL
Vd (L)
Cp at 1 hour  -------
ug-
 mL
Cpmax  --------
ug
 mL
Tmax (hr)
1. MRT iv
3. t1 ⁄ 2

Oral Dosing
4. Cp 0
5. Vd
6. The plasma concentration ( Cp ) of verapamil at 1 hour after the iv dose was given.
8. f , the absolute bioavailability of oral verapamil.

Oral Dosing
Zidovudine (Problem 8 - 9)
Trang, J., et al., "Zidovudine bioavailability and linear pharmacokinetics in female B6C3F1 mice", Drug Metabolism and Disposi-
tion Vol, 21 (1993), p.189 - 193.
Zidovudine (AZT) is a potent inhibitor of HIV-1 during viral replication. It has been approved for the treat-
ment of AIDS. In this study a 30 mg/kg dose of AZT was given to mice either iv or orally. :A summary of the some
of data obtained from this experiment is given below.

Dose (mg/kg)
AUC  -------
ug- ⋅ hr
 mL 
AUMC  -------
ug- ⋅ hr 2
 mL 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  --------
ug
 mL
Vd (L)
Cp at 1 hour  -------
ug-
 mL
Cpmax  --------
ug
 mL
Tmax (hr)
1. MRT iv
3. t1 ⁄ 2
4. Cp 0

Oral Dosing
5. Vd
6. The plasma concentration ( Cp ) of zidovudine at 1 hour after the iv dose was given.
8. f , the absolute bioavailability of oral zidovudine.

9 MRT oral .
10. MAT oral

CHAPTER 8 Bioavailability, Bioequivalence,
and Drug Selection
Author: Rasma Chereson

Reviewer: Umesh Banakar
OBJECTIVES
1. Given sufficient data to compare an oral product with another oral product or an
IV product, the student will estimate (III) the bioavailability (compare AUCs) and
judge (VI) professional acceptance of the product with regard to bioequivalence
(evaluate (VI) AUC, T p and ( Cp ) max ).
3. The student will be able to calculate (III) the absolute bioavailability of drug prod-
ucts.
4. The student will be able to discuss (II) the various factors affecting bioavailability.
5. The student will be able to discuss (II) the various methods of assessing bioavail-
ablity.
6. The student will be able to discuss (II) In Vivo / In Vitro Correlations.
7. The student will be able to enumerate (II) FDA requirements regarding bioequiva-
lence.
8. The student shall be able to utilize (III) the FDA “Orange Book” to make drug
product selections.
9. The student shall be able to discuss (II) and utilize (III) reasonalble guidelines
regarding drug product selections.

Bioavailability, Bioequivalence, and Drug Selection
8.1 Bioavailability, Bioequivalence and Drug Product Selection

Bioavailability and bioequivalence of drug products, and drug product selection
have emerged as critical issues in pharmacy and medicine during the last three
decades. Concern about lowering health care costs has resulted in a tremendous
increase in the use of generic drug products; currently about one half of all pre-
scriptions written are for drugs that can be substituted with a generic product (1).
Over 80% of the approximately 10,000 prescription drugs available in 1990 were
available from more than one source (2). With the increasing availability and use
of generic drug products, health care professionals are confronted with an
ever-larger array of multisource products from which they must select those that
are therapeutically equivalent.
This phenomenal growth of the generic pharmaceutical industry and the abun-
dance of multisource products have prompted some questions among many health
professionals and scientists regarding the therapeutic equivalency of these prod-
ucts, particularly those in certain critical therapeutic categories such as anticonvul-
sants and cardiovasculars (1, 3-5). Inherent in the currently accepted guidelines
for product substitution is the assumption that a generic drug considered to be
bioequivalent to a brand-name drug will elicit the same clinical effect. As straight-
forward as this statement regarding bioequivalence appears to be, it has generated
a great deal of controversy among scientists and professionals in the health care
field. Numerous papers in the literature indicate that there is concern that the cur-
rent standards for approval of generic drugs may not always ensure therapeutic
equivalence (6-18).
The availability of different formulations of the same drug substance given at the
same strength and in the same dosage form poses a special challenge to health care
professionals, making these issues very relevant to pharmacists in all practice set-
tings. Since pharmacists play an important role in product-selection decisions,
they must have an understanding of the principles and concepts of bioavailability
and bioequivalence.
8.1.1 RELATIVE AND ABSOLUTE BIOAVAILABILITY
Bioavailability is a pharmacokinetic term that describes the rate and extent to

which the active drug ingredient is absorbed from a drug product and becomes
available at the site of drug action. Since pharmacologic response is generally
related to the concentration of drug at the receptor site, the availability of a drug
from a dosage form is a critical element of a drug product's clinical efficacy. How-
ever, drug concentrations usually cannot be readily measured directly at the site of

action. Therefore, most bioavailability studies involve the determination of drug

concentration in the blood or urine. This is based on the premise that the drug at
the site of action is in equilibrium with drug in the blood. It is therefore possible to
obtain an indirect measure of drug response by monitoring drug levels in the blood
or urine. Thus, bioavailability is concerned with how quickly and how much of a
drug appears in the blood after a specific dose is administered. The bioavailability
of a drug product often determines the therapeutic efficacy of that product since it
affects the onset, intensity and duration of therapeutic response of the drug. In
most cases one is concerned with the extent of absorption of drug, (that is, the frac-
tion of the dose that actually reaches the bloodstream) since this represents the
"effective dose" of a drug. This is generally less than the amount of drug actually
administered in the dosage form. In come cases, notably those where acute condi-
tions are being treated, one is also concerned with the rate of absorption of a drug,
since rapid onset of pharmacologic action is desired. Conversely, these are
instances where a slower rate of absorption is desired, either to avoid adverse
effects or to produce a prolonged duration of action.
"Absolute" bioavailability, F, is the fraction of an administered dose which actually

reaches the systemic circulation, and ranges from F = 0 (no drug absorption) to F =
1 (complete drug absorption). Since the total amount of drug reaching the sys-
temic circulation is directly proportional to the area under the plasma drug concen-
tration as a function of time curve (AUC), F is determined by comparing the
respective AUCs of the test product and the same dose of drug administered intra-
venously. The intravenous route is the reference standard since the dose is, by def-
inition, completely available.
AUC ev
F = ----------------
- (EQ 8-1)
AUC iv
(where AUCEV and AUCIV are, respectively, the area under the plasma concentra-
tion-time curve following the extravascular and intravenous administration of a
given dose of drug. Knowledge of F is needed to determine an appropriate oral
dose of a drug relative to an IV dose.
"Relative" or “Comparative” bioavailability refers to the availability of a drug

product as compared to another dosage form or product of the same drug given in
the same dose. These measurements determine the effects of formulation differ-
ences on drug absorption. The relative bioavailability of product A compared to
product B, both products containing the same dose of the same drug, is obtained by
comparing their respective AUCs.
AUC
RelativeBioavailabilty = ---------------A (EQ 8-2)
AUC B

where drug product B is the reference standard. When the bioavailability of a

generic product is considered, it is usually the relative bioavailability that is
referred to. A more general form of the equation results from considering the pos-
sibility of different doses,
AUC Generic
-----------------------------
Dose Generic
ComparativeBioavailability = ----------------------------- (EQ 8-3)
AUC Brand
-------------------------
Dose Brand
The difference between absolute and relative bioavailability is illustrated by the

following hypothetical example. Assume that an intravenous injection (Product
A) and two oral dosage forms (Product B and Product C), all containing the same
dose of the same drug, are given to a group of subjects in a crossover study. Fur-
thermore, suppose each product gave the values for AUC indicated in Table 8-1 on
page 4.
TABLE 8-1. Data for Absolute and Relative Bioavailability
Drug Product Area Under the Curve (mcg/ml) x hr
A Intravenous injection 100
B Oral dosage form, brand or reference standard 50
C Oral dosage form, generic Product 40
The F for Product B and Product C is 50% (F = 0.5) and 40% (F = 0.4), respec-
tively. However, when the two oral products are compared, the relative bioavail-
ability of Product C as compared to Product B is 80%.
8.1.2 FACTORS INFLUENCING BIOAVAILABILITY
Before the therapeutic effect of an orally administered drug can be realized, the
drug must be absorbed. The systemic absorption of an orally administered drug in
a solid dosage form is comprised of three distinct steps:
1. disintegration of the drug product
2. dissolution of the drug in the fluids at the absorption site
3. transfer of drug molecule across the membrane lining the gastrointestinal tract into the systemic
circulation.

Any factor that affects any of these three steps can alter the drug's bioavailability
and thereby its therapeutic effect. While there are more than three dozen of these
factors that have been identified (19-38), the more significant ones are summarized
here.
The various factors that can influence the bioavailability of a drug can be broadly
classified as dosage form-related or patient-related. Some of these factors are
listed in Table 8-2 on page 5 and Table 8-3 on page 5, respectively.
TABLE 8-2 Bioavailability Factors related to the dosage form
Physicochemical properties of the drug Formulation and manufacturing variables

Particle size Amount of disintegrant
Crystalline structure Amount of lubricant
Degree of hydration of crystal Special coatings
Salt or ester form Nature of diluent
Compression force
TABLE 8-3 Bioavailability Factors Related to the patient
Physiologic factors Interactions with other substances

Variations in absorption power along GI tract Food
Variations in pH of GI fluids Fluid volume
Gastric emptying rate Other drugs
Intestinal motility
Perfusion of GI tract
Presystemic and first-pass metabolism
Age, sex, weight
Disease states
The physical and chemical characteristics of a drug as well as its formulation are
of prime importance in bioavailability because they can affect not only the absorp-
tion characteristics of the drug but also its stability. Since a drug must be dissolved
to be absorbed, its rate of dissolution from a given product must influence its rate
of absorption. This is particularly the case for sparingly soluble drugs. All the fac-
tors listed in Table 8-2 on page 5 can alter the dissolution rate of the drug, its bio-
availability, and ultimately, its therapeutic performance.
One of the more important factors that affects the dissolution rate of slowly dis-
solving substances is the surface area of the dissolving solid (39). Peak blood lev-
els occurred much faster with the smaller particles than the larger ones, primarily

as a result of their faster dissolution rate. Particle size can also have a significant
effect on AUC(40). Serum levels of phenytoin after administration of equal doses
containing micronized (formulation G) and conventional (formulation F) drug
were measured. Based on the AUC, almost twice as much phenytoin was
absorbed after the micronized preparation (40).
There are numerous reports of the effects of formulation and processing variables
on the dissolution of active ingredients from drug products; an apparently inert
ingredient may affect drug absorption. For example, magnesium stearate, a lubri-
cant, commonly used in tablet and capsule formulations, is water-insoluble and
water-repellent. Its hydrophobic nature tends to retard drug dissolution by pre-
venting contact between the solid drug and the aqueous GI fluids. Thus, increas-
ing the amount of magnesium stearate in the formulation results in a slower
dissolution rate of the drug, and decreased bioavailability(34) .
The nature of the dosage form itself may have an effect on drug absorption charac-
teristics. The major pharmaceutical dosage forms for oral use are listed in Table 8-
4 on page 6 in order of decreasing bioavailability of their active ingredients. The
decreasing bioavailability is related to the number of steps involved in the absorp-
tion process following administration. The greater the number of steps a product
must undergo before the final absorption step, the slower is the availability and the
greater is the potential for bioavailability differences to occur. Thus, solutions
(elixirs, syrups, or simple solutions) generally result in faster and more complete
absorption of drug, since a dissolution step is not required. Enteric-coated tablets,
on the other hand, do not even begin to release the drug until the tablets empty
from the stomach, resulting in poor and erratic bioavailability.
TABLE 8-4 Bioavailability and oral Dosage Forms
Fastest availability Solutions

Suspensions
Capsules
Tablets
Coated tablets
Slowest availability Controlled-release formulations
Bioavailability studies with pentobarbital from various dosage forms show the
absorption rate of pentobarbital after administration in various oral dosage forms
decreased in the following order: aqueous solution > aqueous suspension of the
free acid > capsule of the sodium salt > tablet of the free acid (41).
In addition to the dosage form-related factors identified above, bioavailability may

also be affected by a variety of physiologic and clinical factors related to the
patient (Table 8-3 on page 5). Considerable inter-subject differences in the bio-

availability of some drugs have been observed. These can often be attributed to
individual variations in such factors as GI motility, disease state and concomi-
tantly-administered food or drugs.
One example of the myriad of physiologic factors that can affect the bioavailability
of an orally-administered drug is a patient's gastric emptying rate. Since the prox-
imal small intestine is the optimum site for drug absorption, a change in the stom-
ach emptying rate is likely to alter the rate, and possibly the extent, of drug
absorption. Any factor that slows the gastric emptying rate may thus prolong the
onset time for drug action and reduce the therapeutic efficacy of drugs that are pri-
marily absorbed from the small intestine. In addition, a delay in gastric emptying
could result in extensive decomposition and reduced bioavailability of drugs that
are unstable in the acidic media of the stomach (e.g. penicillins and erythromycin).
Differences in stomach emptying among individuals have been implicated as a

major cause of variations in the bioavailability of some drugs, particularly those
with acid-resistant enteric coatings. In a study (42), after the administration of 1.5
g acetaminophen to 14 patients, the maximum plasma concentration ranged from
7.4 to 37 mcg/ml, and the time to reach the maximum concentration ranged from
30 to 180 minutes. Both these parameters of bioavailability were linearly related
to the gastric emptying half-life found in each patient.
There are numerous factors that affect gastric emptying rate (Table 8-5 on page 8)
(43). Factors such as a patient's emotional state, certain drugs, type of food
ingested and even a patient's posture can alter the time course and extent of drug
absorption.

TABLE 8-5 Factors influencing Gastric Emptying Rate
INFLUENCE ON GASTRIC
FACTOR EMPTYING RATE
Increased viscosity of stomach contents decreased
Body position
lying on left side decreased
Emotional state
stress increased or decreased
depression decreased
anxiety increased
Activity, exercise decreased
Type of meal
fatty acids, fats decreased
carbohydrates decreased
amino acids decreased
pH of stomach contents
decreased decreased
increased increased
Disease states
gastric ulcers decreased
Crohn's disease decreased
hypothyroidism decreased
hyperthyroidism increased
Drugs
atropine decreased
propantheline decreased
narcotic analgesics decreased
amitriptyline decreased
metoclopramide increased
Since drugs are generally administered to patients who are ill, it is important to
consider the effects of the disease process on the bioavailability of the drug. Dis-
ease states, particularly those involving the GI tract, such as celiac disease, Crohn's
disease, achlorhydria, and hypermotility syndromes can certainly alter the absorp-
tion of a drug (32). In addition, some diseases concerning the cardiovascular sys-
tem and the liver may also alter circulating drug levels after oral dosing.
Drugs are frequently taken with food, and patients often use mealtimes to remind
them to take their medications. However, food can have a significant effect on the
bioavailability of drugs. The influence of food on drug absorption has been recog-

nized for some time, and several reviews have been published on the influence of
food on drug bioavailability (30-32, 36, 44). Food may influence drug absorption
indirectly, through physiological changes in the GI tract produced by the food,
and/or directly, through physical or chemical interactions between the drug mole-
cules and food components. When food is ingested, stomach emptying is delayed,
gastric secretions are increased, stomach pH is altered, and splanchnic blood flow
may increase. These may all affect bioavailability of drugs. Food may also inter-
act directly with drugs, either chemically (e.g. chelation) or physically, by adsorb-
ing the drug or acting as a barrier to absorption. In general, gastrointestinal
absorption of drugs is favored by an empty stomach, but the nature of drug-food
interactions is complex and unpredictable; drug absorption may be reduced,
delayed, enhanced or unaffected by the presence of food. Table 8-6 on page 9
summarizes some of the studies that have indicated the effect of food on the bio-
availability of a variety of drugs.
TABLE 8-6 Effect of Food on Drug Absorption
Reduced Absorption Delayed Absorption Increased Absorption

Ampicillin Acetaminophen Chlorothiazide
Aspirin Aspirin Diazepam
Atenolol Cephalosporins (most) Griseofulvin
Captopril Diclofenac Hydralazine
Erythromycin Digoxin Labetalol
Ethanol Furosemide Metoprolol
Hydrochlorothiazide Nitrofurantoin Nitrofurantoin
Penicillins Sulfadiazine Propranolol
Tetracyclines (most) Sulfisoxazole Riboflavin
Source: Ref. 32
The effect of food and type of diet on the bioavailability of erythromycin is shown
in a study by Welling (45). The absorption of the antibiotic is significantly
reduced when it is administered with food compared with its absorption under fast-
ing conditions. This reduced absorption is primarily a result of degradation of the
acid-labile erythromycin due to prolonged retention in the stomach.
Delayed absorption due to food has been demonstrated in the case of cephradine in
a study by Mischler (46). Similar results have been observed with other oral ceph-
alosporins.
Some drugs demonstrate enhanced bioavailability in the presence of food. This

has been attributed to a variety of factors, including improved compound solubility
and more time for dissolution because of delayed gastric emptying. In the case of

highly metabolized agents, such as propranolol and metoprolol, the enhanced

availability may be due to increased splanchnic blood flow causing reduced
first-pass clearance. The circulating levels of these drugs dosed under fasting and
non-fasting conditions have been presented in a study by Melander (47).
The volume of fluid with which an orally administered dose is taken can also affect
a drug's bioavailability. Drug administration with a larger fluid volume will gener-
ally improve its dissolution characteristics and may also result in more rapid stom-
ach emptying. Thus, more efficient and more reliable drug absorption can be
expected when an oral dosage form is administered with a larger volume of fluid.
(45) .
Interactions between drugs can have a significant effect on the bioavailability of

one or both drugs. Such interactions may be direct, as in chelation of tetracycline
by polyvalent metal ions in antacids or the adsorption of digoxin by
cholestyramine resin, or indirect, as with the increased rate of acetaminophen
absorption due to the increased gastric emptying rate produced by metoclopra-
mide. Most of the reported drug-drug interactions have resulted in a reduction in
the rate and/or extent of drug absorption, the most frequent causes being complex-
ing of a drug with other substances, reduced GI motility and alterations in drug
ionization (24, 30, 32, 48, 49). Table 8-7 on page 10 summarizes the major mech-
anisms of GI drug interactions affecting bioavailability.
TABLE 8-7 Drug interactions affecting absorption
1. Change in gastric or intestinal pH

2. Change in gastrointestinal motility
3. Change in gastrointestinal perfusion
4. Interference with mucosal function (drug-induced malabsorption syndromes)
5. Chelation
6. Exchange resin binding
7. Aadsorption
8. Solution in poorly absorbable liquid
Source: Ref. 23
An example of a direct interaction between drugs affecting bioavailability is the

interaction between iron and tetracycline. This is a well-documented and clini-
cally significant interaction which can result in a dramatic reduction in serum con-
centration of tetracycline (50).
The above potential sources of alteration in a drug's bioavailability must be kept in

mind when attempting to evaluate the relative performance of drug products on the

basis of studies performed with healthy human volunteers. These studies are gen-
erally performed under tightly-controlled fasting conditions in the absence of other
drugs. In practice, however, drugs are seldom taken under such ideal conditions,
and the factors leading to changes in drug absorption must be taken into consider-
ation.
8.1.3 METHODS OF ASSESSING BIOAVAILABILITY
Bioavailability testing is a means of predicting the clinical efficacy of a drug; the

estimation of the bioavailability of a drug in a given dosage form is direct evidence
of the efficiency with which a dosage form performs its intended therapeutic func-
tion.
The bioavailability of a drug substance formulated into a pharmaceutical product

is fundamental to the goals of dosage form design and essential for the clinical effi-
cacy of the medication. Thus, bioavailability testing, which measures the rate and
extent of drug absorption, is a way to obtain evidence of the therapeutic utility of a
drug product. Bioavailability determinations are performed by drug manufacturers
to ensure that a given drug product will get the therapeutic agent to its site of
action in an adequate concentration. Bioavailability studies are also carried out to
compare the availability of a drug substance from different dosage forms or from
the same dosage form produced by different manufacturers.
In-vivo methods One method for assessing the bioavailability of a drug product is through the dem-
onstration of a clinically significant effect. However, such clinical studies are
complex, expensive, time-consuming and require a sensitive and quantitative mea-
sure of the desired response. Further, response is often quite variable, requiring a
large test population. Practical considerations, therefore, preclude the use of this
method except in initial stages of development while proving the efficacy of a new
chemical entity.
Quantification of pharmacologic effect is another possible way to assess a drug's

bioavailability. This method is based on the assumption that a given intensity of
response is associated with a particular drug concentration at the site of action;
e.g., variation of miotic response intensity can be directly related to the oral dose
of chlorpromazine. However, monitoring of pharmacologic data is often difficult,
precision and reproducibility are difficult to establish, and there are only a limited
number of pharmacologic effects (e.g. heart rate, body temperature, blood sugar
levels) that are applicable to this method.
Because of these limitations, alternative methods have been developed to predict

the therapeutic potential of a drug. The current method to assess the clinical per-
formance of a drug involves measurement of the drug concentrations in the blood

or urine. In such studies a single dose of the drug product is administered to a

panel of normal, healthy adult (18- to 35-year old) subjects. Blood and/or urine
samples are collected over a period of time following administration and are ana-
lyzed for drug content. Based on the blood concentration as a function of time
and/or urinary excretion profile, inferences are drawn regarding the rate and extent
of absorption of the drug. These studies are relatively easy to conduct and require
a limited number of subjects.
Blood level studies- Blood level studies are the most common type of human bioavailability studies,
and are based on the assumption that there is a direct relationship between the con-
centration of drug in blood or plasma and the concentration of drug at the site of
action. By monitoring the concentration in the blood, it is thus possible to obtain
an indirect measure of drug response. Following the administration of a single
dose of a medication, blood samples are drawn at specific time intervals and ana-
lyzed for drug content. A profile is constructed showing the concentration of drug
in blood at the specific times the samples were taken . The key parameters to note
are:
∞
1. AUC , The area under the plasma concentration-time curve, The AUC is proportional to the
0
total amount of drug reaching the systemic circulation, and thus characterizes the extent of
absorption.
2. Cmax , The maximum drug concentration. The maximum concentration of drug in the plasma
is a function of both the rate and extent of absorption. Cmax will increase with an increase in
the dose, as well as with an increase in the absorption rate.
3. Tmax , The time at which the Cmax occurs. The Tmax reflects the rate of drug absorption, and
decreases as the absorption rate increases.
Bioavailability (the rate and extent of drug absorption) is generally assessed by the
determination of these three parameters.
Since the AUC is representative of, and proportional to, the total amount of drug
absorbed into the circulation, it is used to quantitate the extent of drug absorption.
The calculation of AUC has been discussed in Chapter 4. A variety of pharmacok-
inetic methods have been suggested for the calculation of absorption rates (51-56).
For clinical purposes, it is generally sufficient to determine Cmax and Tmax. If all
other factors are constant, such as the extent of absorption and rate of elimination,
then Cmax is proportional to the rate of absorption and Tmax is inversely propor-
tional to the absorption rate. Thus, the faster the absorption of a drug the higher
the maximum concentration will be and the less time it will take to reach the max-
imum concentration.
Urinary Excretion Data - An alternative bioavailability study measures the cumulative amount of unchanged
drug excreted in the urine. These studies involve collection of urine samples and
the determination of the total quantity of drug excreted in the urine as a function of

time. These studies are based on the premise that urinary excretion of the
unchanged drug is directly proportional to the plasma concentration of total drug.
Thus, the total quantity of drug excreted in the urine is a reflection of the quantity
of drug absorbed from the gastrointestinal tract. Consider the following example:
two products, A and B, each containing 100 mg of the same drug are administered
orally. A total of 80 mg of drug is recovered in the urine from Product A, but only
40 mg is recovered from Product B. This indicates that twice as much drug was
absorbed from Product A as from Product B. (The fact that neither product
resulted in excretion of the entire dose might be due to the existence of other routes
of elimination, e.g. metabolism).
This technique of studying bioavailability is most useful for those drugs that are
not extensively metabolized prior to urinary elimination. As a rule-of-thumb,
determination of bioavailability using urinary excretion data should be conducted
only if at least 20% of a dose is excreted unchanged in the urine after an IV dose
(56). Other conditions which must be met for this method to give valid results
include:
1. the fraction of drug entering the bloodstream and being excreted intact by the kidneys must
remain constant.
2. collection of the urine has to continue until all the drug has been completely excreted (five times
the half-life 1).
Urinary excretion data are primarily useful for assessing extent of drug absorption,
although the time course for the cumulative amount of drug excreted in the urine
can also be used to estimate the rate of absorption. In practice, these estimates are
subject to a high degree of variability, and are less reliable than those obtained
from plasma concentration-time profiles (57). Thus, urinary excretion of drug is
not recommended as a substitute for blood concentration data; rather, these studies
should be used in conjunction with blood level data for confirmatory purposes.
Single-dose versus Most bioavailability evaluations are made on the basis of single-dose administra-
Multiple-Dose- tion. The argument has been made that single doses are not representative of the
actual clinical situation, since in most instances, patients require repeated adminis-
tration of a drug. When a drug is administered repeatedly at fixed intervals, with
the dosing frequency less than five half-lives, drug will accumulate in the body and
eventually reach a plateau, or a steady-state
At steady-state, the amount of drug eliminated from the body during one dosing
interval is equal to the available dose (rate in = rate out); therefore, the area under
the curve during a dosing interval at steady-state is equal to the total area under the
curve obtained when a single dose is administered. This AUC can therefore be
1. Half life is defined as the length of time required to lose 50% of the drug in the body, assuming first order elimination.

used to assess the extent of absorption of the drug, as well as its absolute and rela-
tive bioavailability.
Multiple-dose administration has several advantages over single-dose bioavailabil-

ity studies, as well as some limitations. These are summarized in Table 8-8 on
page 14 (54, 59).
TABLE 8-8 Multiple dose vs. single dose studies in bioavailability studies
Advantages:
• Eliminates the need to extrapolate the plasma concentration profiles to obtain the total AUC
after a single dose
• Eliminates the need for a long wash-out period between doses
• More closely reflects the actual clinical use of the drug
• Allows blood levels to be measured at the same concentrations encountered therapeutically
• Because blood levels tend to be higher than in the single-dose method, quantitative determina-
tion is easier and more reliable
• Saturable pharmacokinetics, if present, can be more readily detected at steady-state
Limitations:
• Requires more time to complete
• More difficult and costly to conduct (requiring prolonged monitoring of subjects
• Greater problems with compliance control
• Greater exposure of subjects to the test drug, increasing the potential for adverse reactions
When a drug obeys linear, first-order kinetics, it is possible to estimate the results
that would be obtained during multiple dosing from single-dose studies. Projec-
tion is easily made with regard to the extent of absorption, using the AUC follow-
ing a single dose. Results from bioequivalence studies indicate that conclusions on
the extent of absorption as assessed by the AUC can be made equally well on the
basis of a single or multiple dose study (60). Assessing the rate of absorption dur-
ing multiple-dosing from single-dose studies has presented a greater problem.
Although a number of single-dose characteristics have been suggested as indica-
tors of rate of absorption during multiple dosing (e.g. percent peak-trough fluctua-
tion and percent peak-trough swing), results of bioequivalence studies indicate that
only the plateau time (the time during which the concentration exceeds 75% of the
maximum concentration, t 75% Cmax) and the residual concentration at the end of
the dose interval produce consistent results in assessing the rate of absorption in
single- and multiple-dose studies (54, 61).
In the case of drugs exhibiting nonlinear kinetics, establishing a linear relationship

between single- and multiple-dose bioavailability data has proven to be a difficult
task. Thus, it has been recommended that for drugs with either saturable elimina-
tion or a nonlinear first-pass effect, steady-state studies be carried out to assess
their bioavailability (62).

8.1.4 STUDY DESIGN
Bioavailability studies involve the administration of the test dosage form to a panel
of subjects, after which blood and/or urine samples are collected and analyzed for
drug content. Based on the concentration profile of the drug, a judgement is made
regarding the rate and extent of absorption of the drug. Normally, the study is con-
ducted in a group of healthy, male subjects who are of normal height and weight,
and range in age from 18 to 35 years (6). Questions have been raised regarding the
extent to which such a population reflects the performance of a given drug product
in a actual patient population. At first glance, it would seem that bioavailability
should be determined in patients actually suffering from the disease for which the
drug is intended, or in patients representative of the age and sex of subjects who
would be using the drug. However, there are several very good reasons for using
healthy volunteers rather than patients. In bioavailability studies, it is assumed
that there are no physiologic changes in the subjects during the course of the study.
If actual patients were used, this would not be a valid assumption, due to possible
changes in the disease state. Another potential problem with using patients is that
many patients take more than one drug. This could result in a drug-drug interac-
tion which could influence the bioavailability of the test drug. In addition, diet and
fluid volume intake, both of which can influence a drug's bioavailability are more
difficult to control in a patient population than in a panel of healthy test subjects.
In general, it is more difficult with patients to have a standardized set of conditions
which are necessary for a dependable bioavailability study. However, it must be
recognized that factors that may affect a drug's performance in a patient population
may not be detected in a group of healthy subjects. Thus, it is best to conduct a
separate study in patients to determine if the disease, for which the drug is intended
to be used, alters the bioavailability of the drug.
Other important considerations in the methodology of a bioavailability study are

sample size, period of trial, and sampling. For statistical purposes, twelve subjects
are considered to be a minimum sample size. Otherwise there will not be enough
data to draw valid conclusions (63). The bioavailability testing period should be of
a sufficient length of time to ensure that drug absorption has been completed. This
length of time is at least three times the half-life of the drug; generally a period of
four to five times the half-life is used (63, 64). Blood samples should be taken
with sufficient frequency to permit an accurate determination of tmax, Cmax and
AUC.
8.1.5 IN-VITRO DISSOLUTION AND BIOAVAILABILITY
Pharmaceutical scientists have for many years been attempting to establish a corre-
lation between some physicochemical property of a dosage form and the biological

availability of the drug from that dosage form. The term commonly used to
describe this relationship is "in-vitro/in-vivo correlation" (65). Specifically, it is
felt that if such a correlation could be established, it would be possible to use
in-vitro data to predict a drug's in-vivo bioavailability. This would drastically
reduce, or in some cases, completely eliminate the need for bioavailability tests.
The desirability for this becomes clear when one considers the cost and time
involved in bioavailability studies as well as the safety issues involved in adminis-
tering drugs to healthy subjects or patients. It would certainly be preferable to be
able to substitute a quick, inexpensive in-vitro test for in-vivo bioavailability stud-
ies. This would be possible if in-vitro tests could reliably and accurately predict
drug absorption and reflect the in-vivo performance of a drug in humans.
Disintegration Tests- The early attempts to establish an indicator of drug bioavailability focused on dis-
integration as the most pertinent in-vitro parameter. The first official disintegra-
tion test appeared in the United States Pharmacopeia (USP) in 1950. However,
while it is true that a solid dosage form must disintegrate before significant disso-
lution and absorption can occur, meeting the disintegration test requirement only
insures that the dosage form (tablet) will break up into sufficiently small particles
in a specified length of time. It does not ensure that the rate of solution of the drug
is adequate to produce suitable blood levels of the active ingredient. Therefore,
while the test for tablet disintegration is very useful for quality control purposes in
manufacturing, it is a poor index of bioavailability.
Dissolution Tests- Since a drug must go into solution before it can be absorbed, and since the rate at
which a drug dissolves from a dosage form often determines its rate and/or extent
of absorption, attention has been directed at the dissolution rate. It is currently
considered to be the most sensitive in-vitro parameter most likely to correlate with
bioavailability.
Official dissolution tests - There are two official USP dissolution methods: Apparatus 1, (basket method),
and Apparatus 2 (paddle method). For details of these dissolution tests, the reader
is recommended to consult USPXXII/NFXVII (66).
Dissolution tests are an extremely valuable tool in ensuring the quality of a drug
product. Generally, product-to-product variations are due to formulation factors,
such as particle size differences, excessive amounts of lubricant and coatings.
These factors are reactive to dissolution testing. Thus, dissolution tests are very
effective in discriminating between and within batches of drug product(s). The
dissolution test, in addition, can exclude definitively any unacceptable product.
Limitations of There are, however, problems with in-vitro dissolution testing which should be
dissolution tests- noted - problems which make correlation with in- vivo availability difficult. The
first is related to instrument variance and the absence of a standard method. The
tests described in the USP are but a few of the large number of dissolution methods
proposed to predict bioavailability. Since the dissolution rate of a dosage form is
dependent on the methodology used in the dissolution test, changes in the appara-

tus, dissolution medium, etc., can dramatically modify the results. Table 8-9 on
page 17 lists some of the factors related to the dissolution testing device that can
affect the dissolution rate of the drug.
TABLE 8-9 Device factors affecting dissolution
1. Degree of agitation
2. Size and shape of container
3. Composition of dissolution medium
• pH
• ionic strength
• viscosity
• surface tension
4. Temperature of dissolution medium
5. Volume of dissolution medium
6. Evaporation
7. Hydrodynamics (flow pattern)
Source: Ref. 67
Another significant problem is related to the difference between the in-vitro and
in-vivo environments in which dissolution occurs. In-vitro studies are generally
carried out under controlled conditions in one, or perhaps two, standardized sol-
vents. The in-vivo environment (the gastrointestinal tract), on the other hand, is a
continuously changing, complex environment. There are many variables which
can affect the dissolution rate of a drug in the gastrointestinal tract, including pH,
enzyme secretions, surface tension, motility, presence of other substances and
absorption surfaces (68). Thus, drugs frequently dissolve in the body at rates quite
different from those observed in an in-vitro test situation. Most of the official dis-
solution tests tend to be acceleration dissolution tests which bear limited or no
relationship with in-vivo dissolution.
Adding to the complexity of correlating dissolution with in-vivo absorption are

factors such as drug-drug interactions, age, food effects, health, genetic back-
ground, biorhythm and physical activity (32, 69). All these factors may have an
effect on the rate and extent of absorption of a drug. Thus, the in-vivo environ-
ment is far more complex, variable, and unpredictable than any in-vitro test envi-
ronment, making in-vitro / in-vivo correlations very difficult. A simple dissolution
test in a standardized vehicle cannot reflect the in vivo absorption of a drug across a
population (70).
Parameters used- Proper selection of the in-vitro and in-vivo parameters to be correlated is critical
in achieving a meaningful correlation. The in-vitro parameter should be selected
that has the greatest effect on the absorption characteristics of the drug (71). There
are several approaches to establishing a correlation between the dissolution of a

drug in in- vitro and the bioavailability of a drug in-vivo. The in-vitro - in-vivo
correlative methods used most often are of the single-point type where the dissolu-
tion rate (expressed as the percent of drug dissolved in a given time, or the time
required for a given percent of the drug to dissolve) is correlated to a certain
parameter of the bioavailability. Examples of in-vivo parameters used include
Cmax, AUC, time to reach half-maximal plasma concentration, the average
plasma concentration after 0.5 or 1 hour, maximum urinary excretion rate, and
cumulative percent excreted in urine after a given time (71- 78). According to
Wagner, the best in-vitro variable to use is the time for 50 percent of the drug to
dissolve, and the best variable from in-vivo data to use is the time for 50 percent of
the drug to be absorbed (79).
Ideally, one would hope to find a linear relationship between some measurement of
the dissolution test and some measurement based on bioavailability studies.
Unfortunately, most attempts to accomplish this objective have failed.
8.1.6 IN-VITRO / IN-VIVO CORRELATION STUDIES-
There have been many attempts to establish in-vitro / in-vivo correlations for a
large variety of drugs. Some of these studies have been summarized by Welling,
Banakar, and Abdou (71, 80-82).
While there are many published examples of satisfactory correlations between

absorption parameters and in-vitro dissolution tests, most studies have resulted in
poor, or moderate, in-vitro - in-vivo correlations, often involving agreement with
only one of the critical bioavailability parameters. Moreover, the positive correla-
tions that have been found generally apply only to the specific formulation studied.
There have been instances where the dissolution rates or various formulations of
the same drug have been significantly different, yet little or no difference was
observed in their bioavailability parameters (83-85). There have also been cases
where a drug has failed to meet compendia dissolution standards but has demon-
strated adequate bioavailability (86). Welling states: "To the writer's knowledge,
there have been no studies that have accurately correlated in- vitro and in-vivo data
to the point that the use of upper and lower limits for in-vitro dissolution parame-
ters can be confidently used to predict in-vivo behavior and, therefore, to replace
in-vivo testing" (71).
Even if an in-vitro test could be designed that would accurately reflect the dissolu-
tion process in the gastrointestinal tract, dissolution is only one of many factors
that affect a drug's bioavailability. For example, saturable presystemic metabolism
may affect the extent of drug absorption, but this would not be predicted by an

in-vitro test. Dissolution studies also would not predict poor bioavailability due to
instability in gastric fluid or complexation with another drug or food component.
Thus, the ultimate evaluation a drug product's performance under the conditions
expected in clinical therapy must be an in-vivo test; a dissolution test is unlikely to
entirely replace bioavailability testing (70, 87, 88). In-vitro methods are important
in the development and optimization of dosage forms while in-vivo tests are essen-
tial in obtaining information on the behavior of medication in living organisms.
One cannot be substituted for the other (69).

8.2 Bioequivalence
Definitions With the phenomenal increase in the availability of generic drugs in recent years,
the issues of bioavailability and bioequivalence have received increasing attention.
In order for a drug product to be interchangeable with the pioneer (innovator or
brand name) product, it must be both pharmaceutically equivalent and bioequiva-
lent to it. According to the FDA, "pharmaceutical equivalents" are drug products
that contain identical active ingredients and are identical in strength or concentra-
tion, dosage form, and route of administration (89). However, pharmaceutical
equivalents do not necessarily contain the same inactive ingredients; various man-
ufacturers' dosage forms may differ in color, flavor, shape, and excipients. The
terms "pharmaceutical equivalents" and "chemical equivalents" are often used
interchangeably.
"Bioequivalence" is a comparison of the bioavailability of two or more drug prod-

ucts. Thus, two products or formulations containing the same active ingredient are
bioequivalent if their rates and extents of absorption are the same. When a new
formulation of an existing drug is developed, its bioavailability is generally evalu-
ated relative to the standard formulation of the originator. Indeed, a bioequiva-
lence trial against the standard formulation is the key feature of an Abbreviated
New Drug Application (ANDA) submitted to the Food and Drug Administration
by a manufacturer who wishes to produce a generic drug. For a generic drug to be
considered bioequivalent to a pioneer product, there must be no statistical differ-
ences (as specified in the accepted criteria) between their plasma concentra-
tion-time profiles. Because two products rarely exhibit absolutely identical
profiles, some degree of difference must be considered acceptable, as will be dis-
cussed later.
Since the concentration of a drug in blood is used as an assessment of its clinical

performance, inherent in the demonstration that two preparations containing
equivalent amounts of the same drug produce similar concentrations of the drug
entity in blood is the assumption that they will elicit equivalent drug responses.
Thus, two products that are deemed to be bioequivalent are also assumed to be
therapeutically equivalent, and therefore interchangeable. This principle is funda-
mental to the concept of bioequivalence and is the basic premise on which it is
founded.
In general, the FDA considers two products to be "therapeutic equivalents" if they

each meet the following criteria (90):
1. they are pharmaceutical equivalents,
2. they are bioequivalent (demonstrated either by a bioavailability measurement or an in vitro stan-
dard),

3. they are in compliance with compendial standards for strength, quality, purity and identity,
4. they are adequately labelled, and
5. they have been manufactured in compliance with Good Manufacturing Practices as established
by the FDA.
Background The first intimations of bioequivalence problems with multi-source drug products
were given by early investigations of the availability of vitamins, aspirin, tetracy-
cline, and tolbutamide (91-97). In 1974, after an extensive review of the bioavail-
ability of drugs, Koch-Weser concluded that " . . . among drugs thus far tested
bioinequivalence of different drug products has been far more common than
bioequivalence" (98). Of particular note were the studies involving digoxin; the
findings of these investigations sparked the discussion about bioequivalence
assessment that still continues today. Significant differences were seen in the bio-
availability of digoxin not only between products supplied by different companies,
but also between lots obtained from the same manufacturer (99). Because of the
narrow therapeutic range for this drug, and because the drug is utilized in the treat-
ment of cardiac patients, these findings generated a great deal of concern.
Similar reports of bioinequivalence and therapeutic inequivalence appeared for

other drugs as well, including phenytoin, phenylbutazone, chloramphenicol, tolb-
utamide and thyroid (6). The clinical significance of these reported differences in
bioavailability relates to the therapeutic index of the drug, the dose of the drug and
the nature of the disease. In 1973 the Ad Hoc Committee on Drug Product Selec-
tion of the American Pharmaceutical Association published a list of drugs with a
potential for therapeutic inequivalence based on reported evidence of bioinequiva-
lence (100). The drugs fall in three categories: "high," "moderate," or "low risk"
based on the clinical implications (Table 8-10 on page 22).

TABLE 8-10 Drugs with various risk potential for inequivalence
High Risk Potential Moderate Risk Potential Low or Negligible Risk

Potential
aminophylline amphetamines acetaminophen
aspirin (when used in high dose (sustained-release) codeine
levels) ampicillin ferrous sulfate
bishydroxycoumarin chloramphenicol hydrochlorothiazide
digoxin chlorpromazine ephedrine
dipheylhydantoin (phenytoin) digitoxin isoniazid
para-aminosalicylic acid erythromycin meprobamate
prednisolone griseofulvin penicillin VK
prednisone oxytetracycline sulfisoxazole
quinidine penicillin G (buffered)
warfarin pentobarbital
phenylbutazone
phenacetin
potassium chloride (solid dosage
forms)
salicylamide
secobarbital
sulfadiazine
tetracycline
tolbutamide
The concern about the bioinequivalence of some drugs led to the establishment in
1974 of the Drug Bioequivalence Study Panel of the Office of Technology Assess-
ment (OTA). The objective was to ensure that drug products of the same physical
and chemical composition would produce similar therapeutic effects. Among the
11 recommendations of the Panel was the conclusion that not all chemical equiva-
lents were interchangeable, but the goal of interchangeability was achievable for
most oral drug products (101). The Report recommended that a system should be
organized as rapidly as possible to generate an official list of interchangeable drug
products. The OTA Report, as well as the growing awareness within the scientific
and regulatory communities of bioavailability problems with marketed drug prod-
ucts, focused the attention of the FDA on bioequivalence and bioavailability prob-
lems and issues.

8.2.1 BIOEQUIVALENCE REGULATIONS
In 1977, the FDA implemented a series of bioavailability and bioequivalence regu-

lations which formed the basis of subsequent discussion, if not controversy, of
therapeutic equivalency of drug products (102). The regulations are divided into
two separate regulations; Subpart B - Procedures for Determining the Bioavail-
ability of Drug Products and Subpart C - Bioequivalence Requirements. While
Table 11 summarizes the key provisions of the bioavailability regulations, those
for bioequivalence requirements are summarized in Table 8-11 on page 23.
TABLE 8-11 Key provisions for bioavailabilty regulations
1. Defines bioavailability in terms of both the rate and extent of drug absorption.
2. Describes procedures for determining the bioavailability of drug products.
3. Sets forth requirements for submission of in vivo bioavailability data.
4. Sets forth criteria for waiver of human in vivo bioavailability studies.
5. Provides general guidelines for the conduct of in vivo bioavailability studies.
6. Imposes a requirement for filing an Investigational New Drug Application.
Source: Ref. 103
Criteria for establishing The 1977 Bioequivalence regulations set forth the following criteria and evidence
a bioequivalence supporting the establishment of a bioequivalence requirement for a given drug
requirement - product:
1. Evidence from well-controlled clinical trials or controlled observations in patients that such
products do not give comparable therapeutic effects.
2. Evidence from well-controlled bioequivalence studies that such products are not bioequivalent
drug products.
3. Evidence that the drug products exhibit a narrow therapeutic ratio, (e.g., there is less than a
two-fold difference in the median lethal dose (LD50) and median effective dose (ED50) value
or have less than a two-fold difference in the minimum toxic concentration and minimum effec-
tive concentrations in the blood), and safe and effective use of the drug product requires careful
dosage titration and patient monitoring.
4. Competent medical determination that a lack of bioequivalence would have a serious adverse
effect in the treatment or prevention of a serious disease or condition.
5. Physicochemical evidence of any of the following:
a. The active drug ingredient has a low solubility in water--e.g., less than 5 mg/ml.
b. The dissolution rate of one or more such products is slow--e.g., less than 50 percent in
thirty minutes when tested with a general method specified by an official compendium or the
FDA.
c. The particle size and/or surface area of the active drug ingredient is critical in determining
bioavailability.

d. Polymorphs, solvates, complexes, and such, exist that could contribute to poor dissolution
and may affect absorption.
e. There is a high excipient/active drug ratio present in the drug product--e.g., greater than 5
to 1.
f. The presence of specific inactive ingredients (e.g. hydrophilic or hydrophobic excipients)
that either may be required for absorption of the active drug or may interfere with such absorp-
tion.
6. Pharmacokinetic evidence of any of the following:
a. The drug is absorbed in large part in a particular segment of the gastrointestinal tract or is
absorbed from a localized site.
b. Poor absorption of the drug, even when it is administered as a solution--e.g., less than 50
percent compared to an intravenous dose.
c. The drug undergoes first-pass metabolism in the intestinal wall or liver.
d. The drug is rapidly metabolized or excreted, requiring rapid dissolution and absorption for
effectiveness.
e. The drug is unstable in specific portions of the gastrointestinal tract, requiring special
coatings and formulations--e.g., enteric coatings, buffers, film coatings--to ensure adequate
absorption.
f. The drug follows nonlinear kinetics in or near the therapeutic range, and the rate and
extent of absorption are both important to bioequivalence.
Types of Bioequivalence In the event that a drug meets one or more of the above six criteria, a bioequiva-
Requirements lence requirement is established. The requirement could be either an in-vivo or an
in-vitro investigation, as specified by the FDA. The types of bioequivalence
requirements include the following:
1. An in-vivo test in humans.
2. An in-vivo test in animals that has been correlated with human in- vivo data.
3. An in-vivo test in animals that has not been correlated with human in- vivo data.
4. An in-vitro bioequivalence standard, i.e., an in-vitro test that has been correlated with human
in-vivo bioavailability data.
5. A currently available in-vitro test (usually a dissolution rate test) that has not been correlated
with human in-vivo bioavailability data.
The regulations state that in-vivo testing in humans would generally be required if
there is well-documented evidence that pharmaceutical equivalents intended to be
used interchangeably meet one of the first three criteria used to establish a
bioequivalence requirement:
1. The drug products do not give comparable therapeutic effects.
2. The drug products are not bioequivalent.
3. The drug products exhibit a narrow therapeutic ratio (as described above), and safe and effec-
tive use of the product requires careful dosage titration and patient monitoring.

Criteria for waiver of Although a human in-vivo test is considered to be preferable to other approaches
evidence of in-vivo for the most accurate determination of bioequivalence, there is a provision in the
bioavailability - 1977 regulations for waiver of an in-vivo bioequivalence study under certain cir-
cumstances. For some drug products, the in-vivo bioavailability of the drug may
be self-evident or unimportant to the achievement of the product's intended pur-
poses. The FDA will waive the requirement for submission of in-vivo evidence of
bioavailability or bioequivalence if the drug product meets one of the following
criteria:
1. The drug product is a solution intended solely for intravenous administration, and contains the
active drug ingredient in the same solvent and concentration as an intravenous solution that is
the subject of an approved full New Drug Application (NDA).
2. The drug product is a topically applied preparation intended for local therapeutic effect.
3. The drug product is an oral dosage form that is not intended to be absorbed, e.g., an antacid.
4. The drug product is administered by inhalation and contains the active drug ingredient in the
same dosage form as a drug product that is the subject of an approved full NDA.
5. The drug product is an oral solution, elixir, syrup, tincture or other similar soluble form, that
contains an active drug ingredient in the same concentration as a drug product that is the subject
of an approved full NDA and contains no inactive ingredient that is known to significantly
affect absorption of the active drug ingredient.
6. The drug product is a solid oral dosage form (other than enteric-coated or controlled-release)
that has been determined to be effective for at least one indication in a Drug Efficacy Study
Implementation (DESI) notice and is not included in the FDA list of drugs for which in vivo
bioequivalence testing is required.
7. The drug product is a parenteral drug product that is determined to be effective for at least one
indication in a DESI notice and shown to be identical in both active and inactive ingredients for-
mulation, with a drug product that is currently approved in an NDA. (Excluded from the waiver
provision are parenteral suspensions and sodium phenytoin powder for injection.)
According to the regulations, the bioavailability of certain drug products may be

demonstrated by evidence obtained in-vitro in lieu of in-vivo data. Thus, the FDA
also permits waiver of the in-vivo requirements if a drug product meets one of the
following criteria:
1. The drug product is one for which only an in-vitro bioequivalence requirement has been
approved by the FDA.
2. The drug product is in the same dosage form, but in a different strength, and is proportionally
similar in its active and inactive ingredients to another drug product made by the same manufac-
turer and the following conditions are met:
a. the bioavailability of this other product has been demonstrated
b. both drug products meet an appropriate in-vitro test approved by the FDA
c. the applicant submits evidence showing that both drug products are proportionally similar
in their active an inactive ingredients.
3. The drug product is shown to meet an in-vitro test that assures bioavailability, i.e., an in-vitro
test that has been correlated with in-vivo data.

4. The drug product is a reformulated product that is identical, except for color, flavor, or preserva-
tive, to another drug product made by the same manufacturer, and both of the following condi-
tions are met:
a. the bioavailability of the other product has been demonstrated.
b. both drug products meet an appropriate in vitro test approved by the FDA.
5. The drug product contains the same active ingredient and is in the same strength and dosage
form as a drug product that is the subject of an approved full NDA or Abbreviated New Drug
Application (ANDA) and both drug products meet an appropriate in-vitro test that has been
approved by the FDA.
Although the above list of criteria for waiver of an in-vivo bioavailability study is
quite lengthy, currently virtually all new tablet or capsule formulations from which
measurable amounts of drug or metabolites are absorbed into the systemic circula-
tion require a human bioequivalence study for approval (104).
TABLE 8-12 Key Provisions for bioequivalence requirements
1. Defines procedures for establishing a bioequivalence requirement.

2. Sets forth criteria to establish a bioequivalence requirement.
3. Describes types of bioequivalence requirements.
4. Sets forth requirement for in-vitro batch testing and certification.
5. Describes requirements for marketing a drug product subject to a bioequivalence requirement.
6. Sets forth requirements for in-vivo testing of a drug product not meeting an in-vitro bioequiv-
alence standard.
Source: Ref. 103
8.2.2 STUDY DESIGN
A single-dose bioequivalency study is generally performed in normal, healthy,

adult volunteers. The subject population should be selected carefully, so that prod-
uct formulations, and not intersubject variations, will be the only significant deter-
minants of bioequivalence (105). A minimum of 12 subjects is recommended,
although 18 to 24 subjects are used to increase the data base for statistical analysis.
The test and the reference products are usually administered to the subjects in the
fasting state (overnight fast for at least 10 hours, plus 2 to 4 hours after administra-
tion of the dose), unless some other approach is more appropriate for valid scien-
tific reasons. These subjects should not take any other medication for one week
prior to the study or during the study. The bioavailability is determined by the col-
lection of either blood samples or urine samples over a period of time and mea-
surement of the concentration of drug present in the samples.
Generally, a crossover study design is used. Using this method, both the test and
the reference products are compared in each subject, so that inter-subject variables,

such as age, weight, differences in metabolism, etc., are minimized. Each subject
thus acts as his own control. Also, with this design, subjects' daily variations are
distributed equally among all dosage forms or drug products being tested.
The subjects are randomly selected for each group and the sequence of drug
administration is randomly assigned. The administration of each product is fol-
lowed by a sufficiently long period of time to ensure complete elimination of the
drug (washout period) before the next administration. The washout period should
be a minimum of 10 half-lives of the administered drug (106). A waiting period of
one week between administration is usually an adequate washout period of most
drugs.
With a drug requiring a washout period of one week, a typical randomized two-
way crossover bioequivalency study is shown in Table 8-13 on page 27.
TABLE 8-13 Two way cross over design
Treatment
Groupa Week 1 Week 2
I A B
II B A
a
10 subjects per group
Assuming that the in-vivo performances of the two formulations are to be com-
pared by examining their blood level profiles, one must be certain that an adequate
number of blood samples are taken. Blood samples should be drawn with suffi-
cient frequency to provide an accurate characterization of the drug concentra-
tion-time profile from which tmax, Cmax and AUC can be determined. Typically,
a total of 10 to 15 sampling times might be required (107). Moreover, all samples
should be taken at the same time for both the test and the reference product to per-
mit proper statistical analysis.
Additional features which contribute to good study design include:

1. All drug samples obtained for the test and reference preparations should be analyzed by the
same method.
2. Identical test conditions must be used for the two groups of subjects. For example, the types of
foods, fluid intake, physical activity, and posture should all be rigidly controlled in the study.
3. The physical characteristics of the subjects (such as age, height, weight, and health) should be
standardized.

Several important questions have been raised specifically regarding the design of
the bioequivalence tests. One of these deals with the selection of the appropriate
reference standard, since this is a critical component of a protocol (6, 108). Nor-
mally, the reference product is that available from the innovator company holding
the New Drug Application. However, in cases where there may be some question
as to the bioavailability of such a product, the study may utilize a solution of the
drug instead of or in addition to the marketed product. The use of a solution can,
of course, result in some difficulty in interpretation of the data: a solid dosage
form, when compared to a solution, will usually exhibit a lower Cmax and a longer
tmax. The clinical significance of these differences may be difficult to assess.
In some instances, the FDA must designate a specific product as the reference
standard from among two or more possible products; e.g., Proventil® tablets, 4 mg
(Schering), not Ventolin® tablets 4 mg (Allen and Hanburys), is the reference
product in bioequivalence studies of albuterol sulfate conventional tablets (108).
Advantages of Multiple- Another important question is whether the bioequivalence trial should compare
dose vs. single dose single doses of the formulations or if it should compare "steady-state" conditions
studies: reached after multiple dosing. It would seem that multiple dosing would be the
logical choice for drugs intended for long-term use since this would give a more
realistic comparison in view of the way in which the drug is normally adminis-
tered. Other advantages of conducting a multiple-dose study over a single-dose
study include (54, 59):
1. Multiple-dosing eliminates the long washout periods required between single-dose administra-
tions. The switch-over from one formulation to the other can take place in steady state.
2. Single-dose studies may pose problems of sufficiently long sampling periods in order to get reli-
able estimates of terminal half-life, which is needed for correct calculation of the total AUC.
3. Multiple-dose studies yield higher concentrations of drug in the blood, making accurate mea-
surement easier. In addition, since drug concentrations need to be measured only over a single
dosing interval at steady state, the need to measure lower concentrations during a disposition
phase is avoided.
4. Multiple-dosing studies can be conducted in patients, rather than healthy volunteers, allowing
the use of higher doses.
5. Usually, smaller intersubject variability is observed in steady-state studies, which may permit
the use of fewer subjects.
6. Nonlinear pharmacokinetics, if present, can be more readily detected at steady-state following
multiple-dosing.
Thus, for some drug products, multiple-dose bioequivalence studies are appropri-
ate and should be performed. In fact, according to one of the conclusions of the
Bio- International '92 conference on the bioequivalence of highly variable drugs, a
multiple-dose study is required in the case of compounds exhibiting nonlinear
pharmacokinetics (110). The circumstances under which a multiple-dose study
may be required are summarized in the regulations (109):

1. When there is a difference in the rate of absorption but not in the extent of absorption.
2. When there is excessive variability in bioavailability from subject to subject.
3. When the concentration of the active moiety in the blood resulting from a single dose is too low
for accurate determination.
4. When the drug product is a controlled-release dosage form.
On the other hand, multiple-dose bioequivalence studies are undesirable in some

respects. Healthy subjects should not be dosed with any drug for an extended
period of time (59). Multiple-dose studies are also generally more difficult to
carry out, especially with regard to ensuring subject compliance with dosing and
dietary restrictions. Therefore, most bioequivalence studies are conducted as sin-
gle-dose studies. Multiple-dose studies should be performed only when a sin-
gle-dose study is not a reliable indicator of bioavailability (111).
8.2.3 ASSESSMENT OF BIOEQUIVALENCE
In order for different formulations of the same drug substance to be considered

bioequivalent, they must be equivalent with respect to the rate and extent of drug
absorption. Thus, the two predominant issues involved in the assessment of
bioequivalence are: the pharmacokinetic parameters that best characterize the rate
and extent of absorption and, the most appropriate method of statistical analysis of
the data.
Pharmacokinetic criteria With regard to the choice of the appropriate pharmacokinetic characteristics,
Westlake suggests comparisons of the formulations should be made with respect to
only those parameter(s) of the blood level profile that possess some meaningful
relation to the therapeutic effect of the drug (107). Since the AUC is directly pro-
portional to the amount of drug absorbed, this pharmacokinetic parameter is most
commonly used to characterize the extent of absorption, both in single- and multi-
ple- dose studies.
The choice of an appropriate pharmacokinetic characteristic for the rate of absorp-

tion is still being discussed with considerable controversy (112, 113). Although a
broad array of methods exists for calculating absorption rates (e.g. moment analy-
sis, deconvolution procedures and curve-fitting), the most commonly used param-
eters are peak concentration (Cmax) and time to peak concentration (tmax).
Although these parameters have been observed to have significant variances and
may be difficult to determine accurately, they remain the parameters generally
requested as rate characteristic by most regulatory authorities for immedi-
ate-release products (112).
Statistical criteria After a bioequivalence study is conducted and the appropriate parameters are
determined, the pharmacokinetic data must be examined according to a set of pre-
determined criteria to confirm or refute the bioequivalency of the test and refer-

ence formulations. That is, one must determine whether the test and reference
products differ within a predefined level of statistical significance. Since the sta-
tistical outcome of a bioequivalence study is the primary basis of the decision for
or against therapeutic equivalence of two products, it is critically important that the
experimental data be analyzed by an appropriate statistical test.
In the early 1970s, bioequivalence was usually determined only on the basis of
mean data. Mean AUC and Cmax values for the generic product had to be within
+20% of those of the reference (innovator) product (108). Although the 20% value
was somewhat arbitrary, it was felt that for most drugs, a 20% change in the dose
would not result in significant differences in the clinical response to drugs (114).
A relatively common misconception is that current regulatory standards still allow
this difference of 20% in the means of the pharmacokinetic variables (Cmax and
AUC) of the test and reference formulations. The FDA's statistical criteria for
approval of generic drugs now requires the application of confidence limits to the
mean data, using an analysis known as the two one-sided tests procedure (115).
This change came about as a result of the conclusion of the FDA Bioequivalence
Task Force in 1986 that the use of a 90% confidence interval based on the two
one-sided t-tests approach was the best available method for evaluating bioequiva-
lence (111).
Westlake was the first to suggest the use of confidence intervals as a means of test-
ing for bioequivalence (116). Recognizing that no two products will result in iden-
tical blood-level profiles, and that there will be differences in mean values between
products, Westlake pointed out that the critical issue was to determine how large
those differences could be before doubts as to therapeutic equivalence arose (107,
117). A test formulation was considered to be bioequivalent to a reference formu-
AUC test Cp max test
lation if 0.8 < ------------------- < 1.2 and 0.8 < -------------------- < 1.2 . (119). By this proce-
AUC ref Cp max ref
dure, if test and reference products were not bioequivalent (i.e. means differed by
more than 20%), there was a 5% chance of concluding that they are bioequivalent.
The current FDA guidelines are that two formulations whose rate and extent of
absorption differ by -20%/+25% or less are generally considered bioequivalent
(90). In order to verify that the -20%/+25% rule is satisfied, the two one-sided sta-
tistical tests are carried out: one test verifies that the bioavailability of the test
product is not too low and the other to show that it is not too high. The current
practice is to carry out the two one-sided tests at the 0.05 level of significance.
Computationally, the two one-sided tests are carried out by computing a 90% con-
fidence interval. For approval of an ANDA, a generic manufacturer must show
that the 90% confidence interval for the ratio of the mean response (usually AUC

and Cmax) of its product to that of the innovator is within the limits of 0.8 to 1.25.
Since these tests are carried out at the 0.05 level of significance, there is no more
than a 5% chance that they will be approved as equivalent if they differ by as much
or more than is allowed by the equivalence criteria (-20%/+25%).
Since this test requires that the 90% confidence interval of the difference between
the means be within a range of -20%/+25%, it is more stringent than simply requir-
ing the comparison of the test and reference products' AUC and Cmax to be within
the 80 to 125% range. If the mean response of the generic product in the study
population is near 20% below or 25% above the innovator mean, one or both of the
confidence limits will fall outside the acceptable range and the product will fail the
bioequivalence test. Thus, the confidence interval requirement ensures that the
difference in mean values for AUC and Cmax will actually be less than -20%/
+25%. It should be pointed out that the standards vary among drugs and drug
classes. For example, antipsychotic agents may fall within a 30% variation and
antiarrhythmic agents may be allowed a 25% variation (122).
The actual differences between brand and generic products observed in bioequiva-
lence studies have been reported to be small. The FDA has stated that for
post-1962 drugs approved over a two-year period under the Waxman-Hatch bill
(1984), the mean bioavailability difference between the generic and pioneer prod-
ucts has been about 3.5% (120). In addition, 80% of the generic drugs approved
by the FDA between 1984 and 1986 differed from the innovator products by an
observed difference of only +5%. Such differences are small when compared to
other variables of drug therapy and would not be expected to produce clinically
observable differences in patient response.
8.2.4 CONTROVERSIES AND CONCERNS IN BIOEQUIVALENCE
The design, performance and evaluation of bioequivalence studies have received a

great deal of attention over the past decade from academia, the pharmaceutical
industry and regulatory agencies. A number of concerns and questions have been
raised about the conduct of bioequivalence studies as well as the guidelines and
criteria used to determine bioequivalence (112). Many of these concerns were trig-
gered by the passage of the Drug Price Competition and Patent Term Restoration
Act (The Waxman-Hatch Amendments) by Congress in 1984. This Act provided
for an expedited approval by the FDA of generic drugs, thereby expanding the
potential generic market for prescription generic drugs (121). Shortly after the
passage of this Act, numerous published reports appeared in the scientific litera-
ture questioning the FDA's ability to ensure that generic drugs were equivalent to
the brand name drugs they were copying. Most of the concerns of the scientific
community centered around adequate standards for evaluation of bioequivalence

and correlation between bioequivalence and therapeutic equivalence. Some of the

issues and concerns that were raised are summarized in Table 8-14 on page 32 (8,
13).
TABLE 8-14 Issues and Concerns regarding bioequivalence
• Correct analysis of drugs in biological fluids

• Appropriate choice of pharmacokinetic parameters to assess bioequivalence
• Generalizing results obtained in healthy volunteers to patients
• Problems involved in extrapolating from single-dose studies to steady-state
• Importance of evaluating active metabolites
• Inadequate statistical criteria to evaluate bioequivalency
• Bioequivalence does not always ensure therapeutic equivalence
• Lack of clear guidelines for evaluation of bioequivalence
At the center of the controversy were the methods and criteria used by the FDA to
determine bioequivalence. Assessment of bioequivalence was done on the basis of
mean data: mean AUC and Cmax values for the generic product had to be within
+20% of those of the innovator product for approval. A statistical test was
employed to assess the power of the test to detect a 20% mean difference in treat-
ments. For drugs that could not meet the statistical criteria because of inherent
variability, another rule was used, the so-called "75/75" rule: that in at least 75%
of the subjects, the test formulation must fall within the range of 75% to 125% of
the reference standard to be considered equivalent (122). It was felt by many that
these rules permitted too much variability in the bioavailability of test drugs and
could result in therapeutic failure or increased risk of side effects (4, 15, 123).
Statistically, the power approach and the 75/75 rule were shown to have poor per-
formance characteristics and bioequivalence evaluation based on these methods
was discontinued by the FDA in 1986. In their place, the Agency currently
employs the two one-sided tests procedure, as previously discussed.
Although the decision of bioequivalence is now made in a more statistically valid

way and the associated concerns have diminished somewhat, some important
questions and controversies in bioequivalence remain. These are primarily cen-
tered around study design, the criteria used to establish or refute equivalence, and
the assumption that products that are bioequivalent are therapeutically equivalent.
One criticism of bioequivalence testing is that it is almost always done in a panel

of young, healthy male volunteers rather than in the target population for which the
drug is intended. Clearly, the performance of a drug product in a 20-year-old male
will not be the same as in an 85-year-old woman. Serious concerns have been

raised that different results would be observed in elderly patients, in women, in

patients with diseases of the gastrointestinal tract, and in patients with diminished
renal or hepatic function. However, although factors such as age and disease state
might affect the actual observed concentrations of drug, the products being com-
pared should be affected in a similar fashion, and one can still be compared to the
other. If two products show an equivalent level in healthy volunteers, their levels
should be elevated to the same extent in patients with impaired hepatic function.
Thus, they can still be compared to each other. Healthy male volunteers are gener-
ally used in bioequivalence studies to assure a homogeneous study population and
to permit focus on formulation factors that might affect bioavailability. In addi-
tion, healthy subjects are more likely to remain stable during the study. The condi-
tion of actual patients might change due to the disease resulting in greater
variability in the data. The FDA does recognize the possibility that some condi-
tions could cause two products that are bioequivalent in healthy subjects to be bio-
inequivalent in certain patients and is prepared to modify its guidelines if
necessary.
A study design-related area of concern is average versus individual bioavailability.

Current procedures assess equivalence in terms of average bioavailabilities, and do
not address within-subject equivalence. In recent years, there has been increased
interest expressed in the variability of response, particularly variability within an
individual. This has given rise to the most recent controversy in bioequivalence
assessment, namely whether average bioequivalence is adequate to allow inter-
changeability of drugs in an individual (112). Anderson and Hauck believe that a
different, more stringent, notion of bioequivalence, referred to as individual
bioequivalence, is needed to provide assurance that an individual patient can be
switched from one formulation to another (124).
The second major area of controversy has focused on the criteria used to determine
bioequivalence. Implicit in the FDA guidelines is the assumption that a -20%/
+25% change in mean serum concentration of drugs can be safely tolerated. How-
ever, there is little documentation demonstrating whether 20% variation in bio-
availabilities does or does not affect the safety and efficacy of drugs. There are
certain critical therapeutic categories (Table 8-15 on page 34) in which minor fluc-
tuations in blood levels may have a substantial impact on therapeutic outcome or
toxicity (125, 126). In view of this, some scientists believe that the FDA should be
more stringent, requiring the mean values for AUC to be within 10% rather than
20%/25%. The Bioequivalence Task Force, in its 1988 report, concluded that for
certain drugs or drug classes, there is clinical evidence that may indicate a need for
tighter limits than the then-generally applied +20% rule (111). The Task Force
recommended that the Agency consider using as an "additional nonstatistical crite-
rion" a mean difference in AUC of +10%; however, this additional criterion would
not be essential to ensuring drug bioequivalence.

TABLE 8-15 Critical Therapeutic Catagories of Drugs
Category Example
Cardiovascular drugs digoxin
Anticonvulsants phenytoin
Bronchodilating agents theophylline
Oral anticoagulants warfarin
In general, the choice of the appropriate bioequivalence range should be done on

clinical grounds; for a drug with a narrow therapeutic range, more stringent limits
should be considered. On the other hand, the current requirements for Cmax for
some drugs may be too stringent, considering the difficulty in accurately estimat-
ing this value. For example, it has been suggested that the acceptable bioequiva-
lence range for Cmax for fast-releasing nifedipine formulations should be 70% to
130%, rather than the usual 80% to 125%. In light of this, many, including the
Pharmaceutical Research and Manufacturers of America (formerly the Pharmaceu-
tical Manufacturers Association [PMA]), feel that the FDA should repudiate its
-20%/+25% rule and develop drug-by- drug bioequivalence criteria (127).
A third source of controversy in bioequivalence is the very foundation on which

the whole concept of bioequivalence is based: the central assumption is that if two
products are shown to be bioequivalent by currently accepted standards, then they
are also therapeutically equivalent, and thus interchangeable. A number of critics
have challenged this "bioequivalence = therapeutic equivalence" equation, point-
ing out that this relationship has not been conclusively established for most drugs
(9, 13, 16, 128). These terms are, in fact, not interchangeable; bioequivalence
means that two products have basically superimposable blood level curves (within
specified limits) while therapeutic equivalence means the products produce similar
effects. There may be situations where two products have similar blood concentra-
tions, yet if the drug has a narrow therapeutic range, they may have significantly
different therapeutic effects. On the other hand, there may be products which have
widely varying blood level profiles, but exhibit very little difference in their clini-
cal effect. This might be the case for drugs with a wide therapeutic range. In addi-
tion, the therapeutic efficacy of some drugs is not necessarily related to their blood
levels, e.g., some psychoactive drugs, where the end point of drug effects is psy-
chological and behavioral response (129).

Williams suggests several ways that the integrity of a bioequivalence study as a

prediction of therapeutic equivalence could be assessed (104). One way involves
the performance of specific clinical studies to confirm that products shown to be
bioequivalent in healthy subjects would be bioequivalent in the patient population
as well. A second way suggested is through post-marketing surveillance of thera-
peutic response produced by different formulations of the same drug under actual
conditions of use. A third method is based on anecdotal reports. Williams points
out that none of these methods have been systematically employed to confirm cur-
rent bioequivalence methodology.
Thus, a number of problems remain in the bioequivalence process which should be

addressed. FDA scientists themselves have readily acknowledged the existence of
shortcomings in the bioequivalence testing program. However, a great deal of
progress has been made in this area in the last twenty years. The improved design
of the studies, the interpretation of the data, the increased scientific rigor of the
acceptance criteria, as well as the more rigorous auditing and inspection program
have made bioequivalence data an appropriate and valid means of approving
generic drug products.
8.2.5 GENERIC DRUGS AND PRODUCT SELECTION
Generic drug utilization has increased dramatically in the last 20 years. In 1975,
approximately 9% of all prescription drugs dispensed were generic versions (130).
This percentage rose to 20% in 1984, and 40% in 1991. It has been variously esti-
mated that the generic share of all new prescriptions will be 46% to 65% in 1995
(131-133).
This rise of generics has not gone altogether smoothly, however; the popularity of
generic drugs took a sharp downturn in 1989 when scandal rocked the generic drug
industry. This involved illegal and unethical acts by some generic drug companies
-- payoffs to FDA employees and fraudulent drug-approval test -- aimed at getting
drugs approved ahead of other firms (134-138).
Although these events did shake the confidence of pharmacists, physicians and the
public in the quality of generic drugs and cast a shadow over generics generally,
these concerns were relatively short-lived. Numerous surveys conducted one to
two years after the scandal unfolded indicated that confidence in generic drugs had
been regained and that the generic industry was in better shape with pharmacists
than it had been before the scandal occurred (139-146). Given the seriousness of
the events, the speed with which generics came back was impressive. This was
due in part to the FDA's reaction to the scandal: a multilevel reorganization of its
generic drug operations and a comprehensive inspection of the leading manufac-

turers of generic drugs (134, 140, 147, 148). It was felt that this stringent FDA
review of generics proved the overall integrity of the companies that emerged with
a clean bill of health. After a sharp drop in the use of generic drugs in 1989, they
began to rise nearly as quickly as they fell, and by mid-1990, sales of generics
were approaching their previous record high (141).
This trend in generic drug utilization is expected to continue its upward spiral, with
newly generic drugs coming to market at an increasing rate. There are several fac-
tors that have contributed to this period of considerable growth in the generic drug
industry. One major factor was the passage of the Drug Price Competition and
Patent Term Restoration Act (Waxman-Hatch Act) in 1984. This act, by eliminat-
ing the requirement for clinical safety and efficacy testing for generics of drugs
introduced after 1962, greatly expedited the entry of generic drugs into the market-
place. The purpose of this act was to facilitate generic competition and thereby
reduce health care costs. This act significantly expanded the number of drugs eli-
gible to be manufactured as generics. Another factor fueling the surge of generic
products is the abundance of brand name drugs whose patents began expiring in
1986. Between 1991 and 1994, patents expired on brand-name drugs whose com-
bined annual sales totaled $10 billion (141). These include Procardia®, Ceclor®,
Tagamet®, Cardizem®, Feldene®, Naprosyn®, and Xanax®. All told, more than
100 drugs worth upwards of $25 billion in sales will have come off patent by the
year 2000 (149). Table 8-16 on page 37 lists some recent and impending patent
expirations (150, 151). As a result of these patent expirations on popular drugs,
there has been an explosion of new generic drug applications.

TABLE 8-16 Recent and pending patent expirations
Brand Name Generic Name Patent Expiration Date*
Procardia Nifedipine 1991

Tenormin Atenolol 1991
Ceclor Cefaclor 1992
Cardizem Diltiazem 1992
Feldene Piroxicam 1992
Naprosyn Naproxen 1993
Xanax Alprazolam 1993
Tagamet Cimetidine 1994
Seldane Terfenadine 1994
Micronase Glyburide 1994
Capoten Captopril 1995
Zantac Ranitidine 1995
Trental Pentoxifylline 1997
Noroxin Norfloxacin 1998
*Extentions may be granted
Perhaps the major factor promoting generic drug utilization is the increased atten-
tion to containing health-care costs. Pushed by a drive for lower-cost medication
by federal and state governments, private insurers, corporate benefit managers,
regulatory agencies and consumer groups, generic drug usage is at a peak. Addi-
tional impetus could come from health care reform, wherein generic drugs are
viewed as a key to controlling pharmaceutical costs. Managed care programs are
expected to cover more than 70% of all outpatient prescriptions by the end of the
decade, with an accompanying greater demand for generic products (152). Thus
the demand for generic drugs will continue to rise, in a climate that favors health
care reform, lower- cost medications and broad-based prescription benefits (153).
With the increasing availability of generic drugs, pharmacists are called upon more
and more often to select a patient's drug product from a myriad of multisource
products. The pharmacist's role in product selection has increased dramatically in
the past decade and the proper selection of multisource drug products has become
a major professional responsibility of pharmacists. Although most pharmacists do
not, realistically, evaluate the bioequivalence of two products from blood level
data, professional judgement does need to be exercised; and this requires an under-
standing and application of the biopharmaceutical principles discussed.

8.2.6 THE ORANGE BOOK
One of the factors that led to the widespread repeal of the state anti-substitution
laws in the 1970's was an effort by the states to contain drug costs and the estab-
lishment of maximum allowable costs (MACs) for reimbursement of drugs under
Medicaid. By allowing the pharmacist to select the manufacturer of a drug, the
less- expensive generic version could be dispensed. However, before the pharma-
cist could knowledgeably select a generic drug, he had to know which generics
were bioequivalent to the innovator product and thus, interchangeable. (There was
substantial evidence at this time that not all pharmaceutically equivalent products
were bioequivalent). To answer this need, the states began preparing either posi-
tive or negative formularies, often turning to the FDA for assistance in this under-
taking.
In response to the many requests for assistance from the states in developing their
formularies, the FDA Commissioner notified state officials of FDA's intent to pro-
vide a list of all prescription drug products that have been approved as being safe
and effective, along with therapeutic equivalence determinations for multisource
prescription products. This list, entitled Approved Drug Products with Therapeu-
tic Equivalence Evaluations, more commonly known as "The Orange Book" was
first published in 1980 and is now in its 14th edition. It is published annually and
updated monthly. The Orange book is generally considered to be the most reliable
guide for determining which drug products are therapeutically equivalent.
The Prescription Drug Products List contains:

1. all the drug products approved by the FDA as being safe and effective under the Federal Food,
Drug and Cosmetic Act, and
2. 2.the therapeutic equivalence evaluations for all approved multisource prescription drug prod-
ucts (those pharmaceutical equivalents available from more than one manufacturer).
Currently, multisource products comprise almost 80% of the approximately 10,000

drugs on the Prescription Drug Product List. The therapeutic evaluation for these
products have been prepared to serve as information and advice to state health
agencies, pharmacists and prescribers to promote knowledgeable drug product
selection and to foster containment of health costs.
8.2.7 THERAPEUTIC EQUIVALENCE
Drug products are considered to be therapeutic equivalents if they are pharmaceu-

tical equivalents and if they can be expected to have the same clinical effect when
administered to patients as specified in the labeling (90). In general, the FDA

evaluates as therapeutically equivalent those drug products that satisfy the follow-
ing general criteria:
1. They are approved as safe and effective.
2. They are pharmaceutical equivalents; i.e. they
a. contain identical amounts of the same active ingredient in the same dosage form and route
of administration, and
b. meet compendial and other applicable standards for quality, purity, strength and identity.
3. They are bioequivalent. Bioequivalence may be established by either an in-vivo or in-vitro test,
depending on the drug. If the drug presents a known or potential bioequivalence problem then
an appropriate standard must be met which demonstrates a comparable rate and extent of
absorption.
4. They are adequately labeled.
5. They are manufactured in compliance with Current Good Manufacturing Practice regulations.
The FDA believes that drug products meeting the above criteria are therapeutically
equivalent and can be substituted with the full expectation that the substituted
product will produce the same therapeutic effect as the prescribed product.
8.2.8 THERAPEUTIC EQUIVALENCE EVALUATION CODES-
The FDA uses a two-letter coding system for multisource products. The first letter
in the code allows users to determine whether a particular product has been evalu-
ated therapeutically equivalent to other pharmaceutically equivalent products. The
second letter in the code provides additional information about the basis of FDA's
evaluation. The various categories are summarized in Table 8-17 on page 40.

TABLE 8-17 Therapuetic equivalency codes
"A" Drug Products "B" Drug Products
Drug products the FDA considers to be therapeutically equivalent; i.e. drug Drug products the FDA does not consider to be therapeutically equivalent; i.e.
products for which: drug products for which actual or potential bioequivalence problems have not
1. There are no actual or potential bioequivalence problems. These are been resolved by adequate evidence of bioequivalence. Often the problem is
designated as: with specific dosage forms rather than with the active ingredient. These products
AA Products in conventional dosage forms are classified as "B" for one of three reasons:
AN Solutions and powders for 1. The active ingredients or dosage forms have documented or potential
aerosolization bioequivalence problems, and no adequate studies demonstrating
bioequivalence have been submitted.
AO Injectable oil solutions
2. The quality standards are inadequate or the FDA has insufficient
AP Injectable aqueous solutions
basis to determine therapeutic equivalence.
AT Topical products
3. The drug product is under regulatory review.
2. Actual or potential bioequivalence problems have been resolved via
These products are designated as:
adequate in vivo and/or in vitro tests. These are designated as AB.
BC Controlled-release tablets, capsules and injectables
BD Active ingredients and dosage forms with documented

bioequivalence problems
BE Delayed-release oral dosage forms (e.g. enteric-coated

products)
BN Products in aerosol-nebulizer drug delivery systems
BP Active ingredients and dosage forms with potential

bioequiva-
lence problems
BR Suppositories or enemas that deliver drugs for systemic

absorption
BS Products having drug standard deficiencies
BT Topical products with bioequivalence issues
BX Insufficient data to determine therapeutic equivalence
B* Drug products requiring further FDA investigation and

review to determine equivalence

There are two basic categories into which multisource drugs have been placed, "A"
or "B". Drug products rated "A" are products that the FDA considers to be thera-
peutically equivalent to the pharmaceutically equivalent original product. These
fall into one of two classes:
1. There are no known or suspected bioequivalence problems.
2. Actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in
vitro evidence supporting bioequivalence.
Category "B" consists of drug products that the FDA does not at this time consider
to be therapeutically equivalent to the pharmaceutically equivalent reference prod-
uct. Certain types of products are rated B by virtue of their specialized dosage
forms. For example, controlled-release dosage forms are rated BC, unless
bioequivalence data have been submitted as evidence of equivalence. In this case,
the product would be coded AB.
The fact that a product is in the "B" category does not mean it should not be dis-
pensed; it simply means that a B rated product should not be substituted for a phar-
maceutically equivalent product. For example, glyburide is marketed as
Micronase® and DiaBeta® by two different manufacturers. Both these products
are clinically effective, but because bioequivalence between the two has not been
studied, they are B rated and are not interchangeable.
To avoid possible significant variations among generic drugs as a result of compar-

ison to different reference drugs, the FDA began designating a single reference
listed drug against which all generic versions must be shown to be bioequivalent.
The reference listed drug is identified by the symbol "+" in the Prescription Drug
Product List. This symbol was used for the first time in the 1993 edition of the
Orange Book.
Limitations and Although the Orange Book is a very valuable reference for pharmacists perform-
exclusions- ing drug product selection, it has certain limitations, which must be recognized. It
was not intended to serve as a single comprehensive reference on all multisource
drugs. Many prescription drug products are not listed in the Orange Book, making
evaluation of their therapeutic equivalence difficult, if not impossible. Exclusion
of a drug from the Orange Book means that the FDA has not evaluated its safety,
efficacy and quality. Table 18 lists the classes of products excluded from the
Orange Book. Because the equivalence of these excluded products is unknown,
interchanging of these products should be avoided.

TABLE 8-18 Drug Products excluded from the Orange Book
1. Drugs marketed before the passage of the Federal Food, Drug, and Cosmetic Act of 1938. These are not
included because the FDA has not reviewed these drugs for safety and efficacy and does not have the necessary
information to make therapeutic equivalence evaluations.
Examples: digoxin, morphine, codeine, thyroid, levothyroxine, phenobarbital and nitroglycerin
2. Drugs for which the FDA has no NDA or ANDA on file.

Examples: Anusol-HC®, Naldecon® (and their generic counterparts)
3. Drugs still undergoing Drug Efficacy Study Implementation (DESI) review. These are drugs that were
marketed between 1938 and 1962 on the basis of safety, but not efficacy. Although most of these drugs have
been reviewed and are listed in the Orange Book, there are still a number of these pre-1962 drugs which have
not yet been classified as "effective" under the DESI program, and are not listed.
Examples: nitroglycerin controlled-release capsules, pentaerythritol tetranitrate, isocarboxazid,
hydrocortisone-iodochlorhydroxyquin cream
In addition, nitroglycerin transdermal patches are still undergoing efficacy studies, and are not listed in the
Orange Book.
Another limitation of the Orange Book that all pharmacists should be aware of is
that the drug listings contain the names of only the companies that actually hold an
approved NDA or ANDA; they may not be the same as the actual manufacturer or
distributor. It is fairly common practice for a drug to be manufactured pursuant to
an NDA or an ANDA but distributed under license agreement by another com-
pany. In this instance, the distributor would not be listed in the Orange Book.
Since pharmacists are, understandably, generally unaware of the name of the actual
holder of the NDA or ANDA, it is often difficult for them to determine the thera-
peutic equivalence of a particular multisource product if it is not listed in the
Orange Book. For example, there are over thirty manufacturers and distributors
marketing approved, therapeutically equivalent versions of furosemide 40 mg tab-
lets (154). However, only twelve of these companies are actually listed in the
Orange book, since these are the actual holders of an NDA or ANDA. Therefore,
the pharmacist would have to verify the therapeutic equivalence evaluation of the
non-listed products by obtaining the information from the manufacturer, packager,
or supplier.
Legal status and The Orange Book per se has no legal status. The FDA stresses that it is a source of
pharmacists' information and advice on drug product selection, but it does not mandate the drug
responsibility- products which may be dispensed nor the products that should be avoided. Thus,
the Orange Book does not carry the weight of regulation or law, and the FDA
assumes no liability for drug products selected on the basis of its equivalence eval-
uation.
The Orange Book points out that "FDA evaluation of therapeutic equivalence in no
way relieves practitioners of their professional responsibilities in prescribing and
dispensing such products with due care." There are circumstances where pharma-

cists will have to exercise professional care and sound judgement in selecting a
drug product for a particular patient. Although two products may be rated as being
therapeutically equivalent in the Orange Book, they may not be equally suitable
for a particular patient. Drugs that share the "A" code may still vary in ways that
could affect patient acceptance. They may differ in shape, color, taste, scoring,
configuration, packaging, preservatives, expiration time, and in some instances,
labeling. If products with such differences are substituted for each other, there is
potential for patient confusion or decreased patient acceptance. For example, a
patient may be sensitive to an inert ingredient in one product that another product
does not contain. Or, a patient may become confused if the color or shape of a
product varies from that to which he has become accustomed. A patient may reject
the administration of a substituted product because of differences in taste or
appearance. When such characteristics of a specific product are important in the
treatment of a particular patient, the pharmacist should select a product with these
considerations in mind as well as bioequivalence.
Despite its limitations and shortcomings, the Orange Book is a very useful guide
for rational product selection. Pharmacists can utilize the information presented
there, in combination with sound professional judgment, to make decisions on
behalf of their patients regarding the choice of the most appropriate drug product.

8.3 Drug Product Selection

Multisource drug product selection has become a very important component of
contemporary pharmacy practice. The National Prescription Audit (NPA) has, for
some years now, been chronicling the heightened role played by pharmacists in the
selection of which brand (or generic version) of a multiple-source drug will be dis-
pensed to the patient. From 1983 through 1993, the pharmacist's role in selecting
brand or generic products for dispensing has increased dramatically, as shown in
Table 19. In the first half of 1993, pharmacists controlled 41% of dispensing deci-
sions, as compared to 16% in 1983. It is evident that the substitution trend is
strong and is continuing to gain ground. This expansion of pharmacy's province in
brand choice decisions is the result of several factors: economic pressures for
lower prescription costs, repeal of anti- substitution laws and increased acceptance
of generics by patients, physicians and pharmacists. Perhaps the most significant
factor in escalating the overall level of pharmacists' brand choice decisions has
been the expiration of the patents of high- volume pioneer brands, as previously
discussed. This has resulted in significant expansion in the potential for pharma-
cist choice.
TABLE 8-19 Pharmacist’s Brand Selection
Year Percent of all new prescriptions involving

pharmacists brand choicea
1983 16
1984 18
1985 20
1986 23
1987 25
1988 27
1989 30
1990 32
1991 34
1992 38
Jan.-June 1993 41

8.3.1 CONSIDERATIONS IN SELECTING A MANUFACTURER
The selection of a pharmaceutical manufacturer of a multisource product has

become an important professional responsibility for pharmacists. This responsibil-
ity has become an especially critical part of a pharmacists role in light of the
increasing number of generic products available and in light of some of the prob-
lems that have occurred in the generic drug industry (the "generic drug scandal" of
1989). The pharmacist is entrusted by the public to select manufacturers that offer
the best quality at the best price.
So how does the phar- Thoughtful selection of a multisource drug product is not an easy task, and
macist select the manu- requires a consideration of not only the drug product itself, but also the manufac-
facturer of a multisource turer, and in some cases, the patient. Several options are open to the pharmacist
drug product? What
performing drug product selection: to select a product solely on the basis of eco-
factors should be con-
sidered? nomics, to select a product on the basis of the reputation of the manufacturer, or to
make a decision based on product bioequivalence and quality and on the basis of
the product's conformity with official compendial standards and with those estab-
lished by the FDA. The first option, while offering a financial advantage, does not
provide assurance of therapeutic efficacy. The second option, although subjective,
is easily applied and does offer a degree of security to the pharmacist. The third
option is the most challenging to the pharmacists, requiring the application of prin-
ciples of biopharmaceutics and pharmacokinetics in arriving at a decision. Ideally,
the pharmacist should take into consideration all the above options when selecting
a drug product for a patient.
When pharmacists were asked which factors are most important to them in select-
ing a manufacturer of a generic product, the primary criteria indicated were the
reputation and quality of the company (159-162). Bioequivalence to the
brand-name product was also ranked as being an important factor in product selec-
tion. However, the most frequently used sources for assessing bioequivalence
were manufacturer reputations (based previous experience) and product literature
provided by the distributing company. Company-sponsored material must be care-
fully evaluated. Unfortunately, promotional literature does not generally contain
sufficient data to permit rational analysis of whether or not products are bioequiva-
lent (163). Also, relying on personal methods of information gathering for assess-
ing bioequivalence is not very reliable. Interestingly, only 23% of pharmacists
reported using the Orange Book in assessing bioequivalence (161). Selection of
drug products should be based on sound scientific and clinical grounds. Develop-
ments in the science of pharmacokinetics and the related area of bioavailability
have given pharmacists the tools necessary to make sound choices among multi-
source products. In response to the profession's need for information and advice
on how to select appropriate drug products from multiple sources, the American
Pharmaceutical Association formed a Bioequivalency Working Group to establish
guidelines for product selection (Table 8-20 on page 47) (164). This Group made

recommendations of factors that pharmacists should consider when selecting drug

products to be dispensed to their patients. If pharmacists consider the factors indi-
cated as part of the professional judgement process when making drug product
selections, it is likely that the best interest of the patients will be served.
The appropriate selection of a generic drug product involves much more than just
cost considerations or reliance on state and federal laws and regulations. It
requires a knowledge of the drug entity and its physical and chemical properties,
the condition to be treated, and its significance, and the history and attitude of the
manufacturer. One of the criteria often used to evaluate a manufacturer's record is
the number and type of recalls of that company's products. Product selection may
also require taking into consideration the patient, the disease, previous drug ther-
apy, and duration of therapy before a decision is made. Gagnon presented a
step-by-step analysis procedure that pharmacists can use in evaluating multisource
suppliers of a pharmaceutical product (Table 8-21 on page 49) (165). Using this
procedure, each manufacturer is rated in each area listed, thus enabling the phar-
macist to make the most rational choice.

TABLE 8-20 Guidelines for product selection
DISPENSING DECISIONS
? State Rules and Regulations. Pharmacists should be cognizant of legal requirements that address the issue of drug product selection. Many states have positive or negative
formularies to provide guidance in drug product selection.
? Bioequivalency Information/Orange Book Ratings. Only products with proven bioequivalency should be selected to be dispensed in lieu of the innovator product.
Products that are listed in the FDA's Approved Drug Products and Therapeutic Equivalence Evaluations (the Orange Book) as "A" rated should be selected when such products
are available. For pre-1938 drugs, the selection should be based on data obtained from the literature, because bioequivalency testing is not required by the FDA for these
drug products.
? Dosage Form. The type of dosage form should be considered whenever one drug product is selected from among multisource drug products. This is especially true with
extended or delayed release medications.
? Previous Drug Use. Two questions should be considered regarding previous drug product usage. First, is the prescribed drug a continuation of already successful therapy?
If it is, the impact of any change in source of the medication should be considered. The pharmacist should also know which product the patient was using previously, including
any medications in the hospital if the patient was recently discharged. Second, was the original product dispensed a generic product? If so, preference should be given to
continuing to dispense the same generic product from the same source.
? Patient Status. The pharmacist should consider how well controlled the patient is and how susceptible that patient might be to small changes in drug absorption. If a
patient has labile control or has experienced great difficulty in achieving control, the pharmacist should continue therapy with a product from a single source throughout therapy.
? Diseases. The seriousness of the disease and its potential impact on the patient may influence the pharmacist's willingness to change products.
? Drug Class or Category. Drugs with narrow therapeutic ranges and with known clinically significant bioavailability problems should be substituted with care and/or after
discussion with the prescriber.
? Cost. The cost of the product , while an important consideration, should be a secondary consideration in selecting among products judged by the pharmacist to be
bioequivalent.
? Patient Opinion. An informed patient, cooperating with a physician and pharmacist in his or her drug therapy, is an important element in ensuring the best possible
therapeutic outcomes. The pharmacist should take into account the patient's need when selecting from multisource drug products and inform the patient of any potential
consequences associated with alternate product selections.
PURCHASE DECISIONS
? Current State Laws and Regulations. Some states have positive or negative formulary systems that place regulatory restrictions on the products considered therapeutically
equivalent. The state formulary may not always be in agreement with classifications listed in the FDA's Orange Book. Therefore, pharmacists should be familiar with both.
? Bioequivalency Information/Orange Book. Products shown to be bioequivalent through reference to the Orange Book or other reliable source of bioequivalency
information are preferred. Purchase decisions for drugs marketed prior to 1938 should be based on data obtained from the literature or the manufacturer, because bioequivalency
testing may not be required by the FDA for these drug products.
? Drug Category. Greater attention should be given to purchasing strategies for drug products used for serious or life-threatening diseases and in situations where therapeutic
activity of the product is confined to a narrow range of biologic fluid concentration.
? Availability. A continuous supply from the same manufacturer is essential even in the event that the distributor has changed to ensure that refills of prescriptions will
contain the same product as originally dispensed. However, in those instances when the manufacturer of a generic drug product has to be changed, care should be exercised
to ensure that the new drug product is equivalent to the formerly stocked drug product.
? Supplier's Reputation. The reputation of the manufacturer in terms of its ability to adhere to good manufacturing practices (GMP) that ensure that each dosage form is
manufactured correctly and in a consistent manner is an important consideration. When purchasing a product from a distributor rather than directly from the manufacturer,
the procedure used by that supplier in selecting manufacturers for multisource products is also an important consideration. Establishment Inspection Reports and recall
reports are available from FDA through a Freedom of Information (FOI) request. These are valuable tools in this decision.
? Cost.


TABLE 8-21 Evaluation of Multi-source Suppliers
Factors and Cues
Product Information
• Size(s) available
• Dosage form(s) available
• Bioequivalence data results using Orange Book
• Existence of identification codes on solid dosage forms
• Average number of months between product receipt and expiration date
• Results of cost-effectiveness information from manufacturer
• Complete product literature provided from manufacturer
• Strength(s) available
• State/federal formulary rules, e.g., MAC limits
Economics
• Price(s)
• Deals and other discounts
• Terms of sale
• Clear and equitable pricing policy
• Large sizes available at discount prices
Product Quality
• NDA/ANDA on file at FDA
• Pharmaceutical elegance of products, e.g., broken tablets, powder in bottles
• Less than 3 year FDA on-site inspection
• Results of on-site FDA inspection
• Company willing to allow pharmacist to inspect plant
• Results of quality control analysis
• Company willing to supply samples for testing
• Product acceptance by physicians
• Product acceptance by patients
Service Quality
• Returns policy
• Rapid resolution of complaints
• Company product availability record
• Liability protection policy
• Terms of unconditional guarantee
• Company commitment to education of practitioners
• Availability of company representative
• Existence of 24-hour emergency customer service telephone number
• Product availability through wholesalers
• Ease of placing orders
• Company customer information center, including an 800 number
Company Reputation
• Number of recalls in last 3 years
• Severity of recalls in last 3 years
• Who initiated recalls (FDA or company)
• Company has a recall strategy
• Other regulatory actions against company
• Company has wide product line
• FDA quality assurance profile
• Company has crisis communication strategy

Pharmacists have the responsibility of correctly selecting and dispensing multi-

source products that will have the greatest likelihood of achieving a positive thera-
peutic outcome in a cost-effective manner. The more information pharmacists
have about a product and its manufacturer, the more likely they will be to make the
most appropriate choice. Price cannot be the single factor in selecting a product. It
is also clear, as Joseph Oddis stated, "Rational drug product selection entails far
more than simply consulting the FDA's Orange Book or looking at the price cata-
logue" (166).
8.3.2 SPECIAL CASES
While in most situations selection of drug products that are therapeutically equiva-
lent can be done without undue complications, there are some circumstances
where problems could occur. Depending on the drug, its formulation, the disease
being treated, and the condition of the patient, generic substitution may not be
advisable. Some of these special situations require extra attention and handling by
the pharmacist.
There are a number of drugs that could present problems when interchanged.
Drugs that are poorly water soluble may have inherent problems with rate and
extent of dissolution, resulting in poor or variable bioavailability. Drugs that are
potent and thus present in very low amounts in a dosage form could present prob-
lems due to formulation factors. Some dosage forms may have inherent bioavail-
ability problems, such as controlled-release products. And drugs which are
considered "critical" also need special consideration. "Critical" drugs have been
defined as drugs with a narrow therapeutic range, where a change in plasma con-
centration might result in adverse clinical outcome; drugs that are considered pri-
marily for control of a disease rather than for alleviation of temporary symptoms;
and drugs that have inherent or historical bioavailability or bioequivalence prob-
lems (8, 19). Seven classes of drugs have been identified that have demonstrated
bioequivalence problems or, because of the nature of the product, have the poten-
tial for creating therapeutic problems if product interchange is permitted (Table 8-
22 on page 51) (167-168).

TABLE 8-22 Catagories of drugs with demonstrated bioequivalence problems
Digitalis glycosides
- digoxin
Warfarin anticoagulants
Theophylline products
Thyroid preparations (including levothyroxine)
Conjugated and esterified estrogens
Antiarrhythmic agents
- quinidine salts
- procainamide
Anticonvulsants
- phenytoin
- carbamazepine
- primidone
There have been numerous reports of drugs implicated in therapeutic problems due
to bioinequivalence difficulties. In addition to those in the categories given in
Table 8-22 on page 51, these include furosemide, propranolol, diazepam, pred-
nisone, nitrofurantoin, and amitriptyline (20, 126, 167, 169-180). Although the
documentation implicating these drugs in therapeutic failures due to bioavailabil-
ity problems is primarily anecdotal in nature (and thus disregarded by the FDA),
the performance of these products should still be closely observed and monitored,
and care should be taken when selecting drugs from these categories.
In addition to "critical" drugs, critical patients and critical diseases have also been
identified when special care should be taken in performing product selection (8,
166). Critical patients are the very old and the very young, those suffering from
multiple diseases who are managed with multiple drugs, and those who live alone,
making observation of adverse drug effects unlikely. Critical diseases are gener-
ally chronic in nature and difficult to stabilize, where drug-disease interactions can
present major problems (e.g. congestive heart failure, asthma, diabetes, cardiac
disorders, and psychoses). In all the above special "critical" circumstances, there
is a high risk of therapeutic problems, and product selection requires extra atten-
tion and precautions. In fact, product substitution and interchange in these cases is
generally discouraged. Once a product (brand or generic) has been selected for a
course of therapy, the pharmacist should not change to a different product if it can
be avoided. If interchange is performed, it should be done only with the utmost
care, and the patient should be monitored for any adverse outcomes.

Pharmacist's Drug product selection has been and continues to be a primary and chal-
professional lenging professional responsibility of pharmacists. It is one where the pharmacist
responsibility- must exercise professional care and sound judgement to make decisions on behalf
of the patient to maximize safety and efficacy, while minimizing cost. Pharmacists
have a professional obligation to patients to take whatever steps are necessary to
assure themselves that the medicines they are dispensing are safe and effective.
Although some of this activity is currently constrained by bureaucratic and regula-
tory restrictions that often discourage, or entirely prevent, individual professional
evaluation and initiative, with a greater appreciation and understanding of the sci-
entific, clinical, and regulatory issues that form the basis of the process, pharma-
cists can make decisions that result in better patient care. Pharmacists must take
steps to ensure the quality and integrity of the drug products dispensed to their
patients. To accomplish this, pharmacists must look to pharmaceutical manufac-
turers to supply them with a quality product they can trust. Thus, the manufacturer
of a multisource product must be carefully selected to ensure that the products they
supply are of proper quality. If necessary, pharmacists should conduct independent
research into the reputation and integrity of the manufacturer, or, if products are
purchased through a buying group, should make sure that established policies and
guidelines are in place to review multisource products. When considering pur-
chasing drug products, the pharmacist should request the manufacturer to provide
certain documentation and information, and should then evaluate this information
(see Table 23).
TABLE 8-23 Considerations when evaluating a Multi-Source vendor
1.Willingness to supply requested information

2.Bioavailability and bioequivalence data
3.Dissolution testing results
4.FDA bioequivalence rating
5.The actual manufacturer of the product, if not the supplier
6.FDA inspection reports
7.History of the manufacturer's recall record
8.Willingness of the manufacturer to permit on-site visitations
9.Evaluate economic considerations such as price, shipping, terms, discounts, insurance, return policies, and packagng.
And finally, pharmacists can counsel the patients on the importance of

using the same drug product throughout a course of therapy, even though they
might go to a different pharmacy. To further emphasize this, it has been suggested
that the initial prescription and subsequent refills of a drug product considered
questionable for interchange should contain auxiliary labeling that stresses the
importance of continuing to use that product (167).
Drug product selection is an important professional responsibility, but it is

not an easy task. It requires the pharmacist to use his/her current knowledge, and

all the currently available information in order to arrive at and render a decision
regarding the most appropriate product to use for a specific patient.

8.4 Summary
With the dramatic increase in the availability and utilization of generic drug prod-
ucts in recent years, pharmacists are being faced with an ever-increasing array of
multisource products. Appropriate selection of a product from the plethora of
products on the market is not always an easy task; the quality of the drug product
must be considered, as well as the cost. The principles of biopharmaceutics indi-
cate that the formulation and method of manufacture of a drug product can have a
marked effect on the bioavailability of the active ingredient. Thus, generic equiva-
lents may not necessarily be therapeutically equivalent. Guidelines and criteria
have been established by the FDA to help judge whether one product can be sub-
stituted for another with assurance of equivalent therapeutic effect.
For pharmacists to provide informed product selection, it is essential that

they be knowledgeable about, and familiar with, these guidelines and criteria. This
requires an understanding of bioavailability, bioequivalence, and how they are
determined. The pharmacist can serve a major role in ensuring that only high qual-
ity products are dispensed, and in this way help reduce health care costs without
compromising quality of care.
Acknowledgment The author gratefully acknowledges the assistance of Umesh V. Banakar in the
preparation of this manuscript.

8.4.1 QUESTIONS
1. The term bioavailability refers to the
a. dissolution of a drug in the gastrointestinal tract.
b. amount of drug destroyed in the liver by first-pass metabolism.
c. distribution of drug to the body tissues over time.
d. relationship between the physical and chemical properties of a drug and its systemic
absorption.
e. measurement of the rate and amount of drug that reaches the systemic circulation.
2. The bioavailability of various drug products can be evaluated by comparing their plasma con-
centration-time curves. The three most important parameters of comparison that can be
obtained directly from the curves are
a. biologic half-life (t1/2), absorption rate constant, area under the curve (AUC).
b. time of peak concentration (tmax), absorption rate constant, elimination rate constant.
c. maximum drug concentration (Cmax), time of peak concentration (tmax), duration of action.
d. area under the curve (AUC), time of peak concentration (tmax), maximum drug concentration
(Cmax).
e. rate of elimination, area under the curve (AUC), rate of absorption.
3. Two products are bioequivalent if they

a. contain the same amount of the same active ingredient.
b. have equal areas under the curve after the administration of the same dose.
c. have the same value for Cmax after administration of the same dose.
d. have equivalent rates and extents of absorption of the drug after administration of equal
doses.
e. are pharmaceutically equivalent.
4. If an oral capsule formulation of drug A produces a plasma concentration- time curve having
the same area under the curve (AUC) as that produced by an equivalent dose of drug A given
intravenously, it can generally be concluded that:
a. there is no advantage to the IV route.
b. the absolute bioavailability of the capsule formulation is equal to 1.
c. the capsule formulation is essentially completely absorbed.
d. the drug is very rapidly absorbed.
e. b and c are correct.
5. 5.Which of the following is NOT a criterion for therapeutic equivalence of two products,
according to the FDA?
a. They must be pharmaceutical equivalents.

b. All ingredients - active and inactive - must be the same.

c. They have been manufactured in compliance with Good Manufacturing Practices.
d. They are bioequivalent.
e. They are approved as safe and effective by the FDA.
6. A test oral formulation has the same area under the plasma concentration- time curve as the ref-
erence formulation. This means that the two formulations
a. are bioequivalent by definition.
b. deliver the same total amount of drug to the body but are not necessarily bioequivalent.
c. are bioequivalent if they both meet USP dissolution standards.
d. deliver the same total amount of drug to the body and are, therefore, bioequivalent.
e. have the same rate of absorption.
7. In-vitro dissolution rate studies on drug products are useful in bioavailability evaluations only if
they can be correlated with
a. in-vivo bioavailability studies in humans.
b. the chemical stability of the drug.
c. USP disintegration requirements.
d. in-vivo studies in at least three species of animals.
e. the therapeutic response observed in patients.
8. Which of the following statements regarding bioequivalence is TRUE?

a. If the mean AUC and Cmax values for a generic product are within + 20% of those of the ref-
erence product, the two products are bioequivalent.
b. If we can be 90% certain that the mean values of AUC and Cmax for two products are within
80% to 125% of each other, then the two products are considered bioequivalent.
c. Bioequivalence studies are generally conducted in a panel of patients consisting of the tar-
get population for which the drug is intended.
d. Bioequivalence studies are generally conducted as multiple-dose studies utilizing the
cross-over design.
e. If two products are shown to be bioequivalent, we can always say with certainty that they
will be therapeutically equivalent.

9. 9.Which of the following statements about the FDA Orange Book is TRUE?
a. Drugs that are excluded from the Orange Book are not safe and effective and should not be
dispensed.
b. It contains therapeutic equivalence evaluations for all the drugs approved by the FDA.
c. Products placed in the "B" category should not be dispensed.
d. The Orange Book is an official compendium, and pharmacists can legally only dispense
those products listed as bioequivalent.
e. The drug listings contain the names of only the companies that actually hold an approved
NDA or ANDA for a drug.
10. 10.Growth in the utilization of generic drug products can be attributed to

a. passage of the 1984 Waxman-Hatch Act.
b. expiration of patents of many popular brand products.
c. pressures to reduce health care costs.
d. the growth of managed health care organizations.
e. all of the above.
8.4.2 ANSWERS TO QUESTIONS
1. e
2. d
3. d
4. e
5. b
6. b
7. a
8. b
9. e
10. e

8.5 Bioavailibility Equations

The following set of equations were used to solve the bioavailability problem set.
The problem sets for the first two drugs have been done for you. The others are
done exactly the same way. The answers follow the problems.
AUMC iv
1. MRT iv = --------------------- as discussed in chapter 4.
AUC iv
1
2. k = ---------------
-
MRT iv
3. ln 2
t 1 ⁄ 2 = --------
k
4. Cp 0iv = AUC ⋅ k
Dose iv
5. Vd = ----------------
-
Cp 0iv
– kt
6. Cp iv = Cp 0 e
AUC oral Dose iv

7. f = --------------------- ⋅ -----------------
Dose oral AUC iv
AUMC po
8. MRT po = ----------------------
- as discussed in chapter 4
AUC po
9. MAT po = MRT po – MRT iv
1
10. k a = ------------
MAT
k
ln  ----a-
k
11. t p = ----------------
ka – k

ka – kt –k t
12. Cp max = fD
------ ⋅ ------------- ⋅ (e p – e a p )
V ka – k
( AUC generic ) ⁄ ( Dose generic )

14. Relative Bioavailability (R.B. or C.B.) = ---------------------------------------------------------------------
-
( AUC Brand ) ⁄ ( Dose Brand )
15. Bioequivalent: Yes if all three:
0.80 < CB < 1.25
t p generic
0.80 < -------------- < 1.25
tp brand
C p max –g eneric
0.80 < -----------------------
- < 1.25
C p max – b rand

8.6 Problems

Caffeine (Problem 8 - 1)
Aramaki, S., et al., "Pharmacokinetics of caffeine and its metabolites in horses after intravenous, intramuscular, or oral adminis-
tration", Chem Pharm Bull, Vol. 30, No. 11, (1991), p. 2999 - 3002.
This study deals with the pharmacokinetics of caffeine. Caffeine doses of 2.5 mg/kg were administered both intrave-
nously and orally to horses with an average weight of about 500 kg. A summary of the some of data obtained from this
experiment is given below. Fill in the empty cells.
TABLE 8-24 Caffeine

Dose (mg/kg) 2.5 2.5 2.5 2.5
63.1 60.7 60 57
AUC  -------- ⋅ hr
ug
 mL 
1442 1556.8 1600 1723

AUMC  -------- ⋅ hr 
ug 2
 mL 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  --------
ug
 mL
Vd (L)
Cp at 1 hour  --------
ug
 mL
Cpmax  -------
ug-
 mL
Tmax (hr)

Cefetamet Pivoxil (Problem 8 - 2)

Ducharme, M., et. al., "Bioavailability of syrup and tablet formulations of cefetamet pivoxil", Antimicrobial Agents and Chemo-
therapy, Vol. 37, No. 12, (1993), p. 2706 - 2709.
Cefetamet pivoxil is a prodrug of cefetamet. This study compares the bioavailability of cefetamet pivoxil in tablet
form versus syrup form. A summary of the some of data obtained from this experiment is given below. Fill in the
approprate cells.
.

Dose (mg) 250 500 500 500
30.64 53.68 50 47
AUC  -------- ⋅ hr
ug
 mL 
101.66 191.64 205.6 225.3

AUMC  -------- ⋅ hr 
ug 2
 mL 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  --------
ug
 mL
Vd (L)
Cp at 1 hour  --------
ug
 mL
Cpmax  -------
ug-
 mL
Tmax (hr)

Cefixime (Problem 8 - 3)
Faulkner, R. ,et al., "Absolute bioavailability of cefixime in man", Journal of Clinical Pharmacology, Vol. 28 (1988), p. 700 - 706.
Cefixime is a broad-spectrum cephalosporin which is active against a variety of gram positive and gram nega-
tive bacteria. In this study, sixteen subjects each received a 200 mg intravenous dose and then a 200 mg capsule with a
washout period between the administration of each dosage form. A summary of the some of data obtained from this
experiment is given below.
Parameter IV Brand Capsule Generic Capsule Bioequivalence

Dose (mg) 200 200 200
47 23.6 20.2
AUC  -------- ⋅ hr
ug
 mL 
183.3 162.8 187.5

AUMC  -------- ⋅ hr 
ug 2
 mL 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  --------
ug
 mL
Vd (L)
Cp at 1 hour  -------
ug-
 mL
Cpmax  --------
ug
 mL
Tmax (hr)

Ceftibuten (Problem 8 - 4)
"The pharmacokinetics of ceftibuten in humans"
Ceftibuten is a new oral cephalosporin with potent activity against enterobacteriaceae and certain gram posi-
tive organisms. In this study two groups received either a 400 mg oral dosage form of ceftibuten or a 200 mg iv bolus
dose of ceftibuten. A summary of the some of data obtained from this experiment is given below.

Dose (mg) 200 400 400 400
75.2 65.9 64.2 64
AUC  -------- ⋅ hr
ug
 mL 
211.2 213.4 220 208

AUMC  -------- ⋅ hr 
ug 2
 mL 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  --------
ug
 mL
Vd (L)
Cp at 1 hour  --------
ug
 mL
Cpmax  --------
ug
mL
Tmax (hr)

Cimetidine (Problem 8 - 5)
Sandborn, W., et al., "Pharmacokinetics and pharmacodynamics of oral and intravenous cimetidine in seriously ill patients", Jour-
nal of Clinical Pharmacology, Vol. 30, (1990), p. 568 - 571.
Cimetidine is a histamine receptor antagonist which is used in the treatment of gastric and duodenal ulcer dis-
ease. In this study, patients received 300 mg of cimetidine as an iv bolus on the first day and data was collected. On
the second day, the patients received 300 mg orally and data was collected. A summary of the some of data obtained
from this experiment is given below.
Parameter IV Brand Tablet Generic Tablet Bioequivalence

Dose (mg) 300 300 300
3.81 2.48 2.50
AUC  -------- ⋅ hr
ug
 mL 
5.33 11.73 10.73

AUMC  -------- ⋅ hr 
ug 2
 mL 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  --------
ug
 mL
Vd (L)
Cp at 1 hour  --------
ug
 mL
Cpmax  --------
ug
mL
Tmax (hr)

Diurnal Variability in Theophylline Bioavailability (Problem 8 - 6)

Bauer, L., Gibaldi, M., and Vestal, R., "Influence of pharmacokinetic diurnal variation on bioavailability estimates", Clinical Phar-
macokinetics, vol. 9, (1984), p. 184 - 187.
This article discusses the effects of diurnal variation on the bioavailability and clearance of theophylline. In
this study patients received a 500 mg dose every 12 hours either orally or by iv bolus. A summary of the some of data
obtained from this experiment for the time period between midnight and noon is given below.

Dose (mg) 500 500 500 500
160.25 144.58 140 144
AUC  -------- ⋅ hr
ug
 mL 
1821 1662 1785 1700

AUMC  -------- ⋅ hr 
ug 2
 mL 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  --------
ug
 mL
Vd (L)
Cp at 1 hour  --------
ug
 mL
Cpmax  --------
ug
mL
Tmax (hr)

cis-5-Fluoro-1-[2-Hydroxymethyl-1,3-Oxathiolan-5-yl] Cytosine
(FTC) (Problem 8 - 7)
Frick, L. , et al., "Pharmacokinetics, oral bioavailability, and metabolic disposition in rats of (-)-cis-5-Fluoro-1-[2-Hydroxyme-
thyl-1,3-Oxathiolan-5-yl] Cytosine, a nucleoside analog active against human immunodeficiency virus and hepatitis B virus", Anti-
microbial Agents and Chemotherapy, Vol. 37, No. 11, (1993), p. 2285 - 2292.
FTC is a 2',3'-didoexynucleoside analog that may be useful against HIV and HBV. In this study, rats with an
average weight of 270 g were given either iv or oral doses of 100 mg/kg. A summary of the some of data obtained

Dose (mg/kg) 100 100 100
265 168 175
AUC  -------- ⋅ hr
ug
 mL 
19514 12600 13125

AUMC  -------- ⋅ hr 
ug 2
mL
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  --------
ug
mL
Vd (L)
Cp at 1 hour  --------
ug
 mL
Cpmax  -------
ug-
 mL
Tmax (hr)

Hydromorphone (Problem 8 - 8)
Vallner, J., et al., "Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to
human subjects", Journal of Clinical Pharmacology, Vol. 21, (1981), p. 152 - 156.
Hydromorphone hydrochloride is an analog of morphine which has about seven times the effect of morphine
when given intravenously. In this study, volunteers were given a 2 mg intravenous dose and a 4 mg oral dose of hydro-
morphone on separate days. A summary of the some of data obtained from this experiment is given below.

Dose (mg) 2 4 4
83 87.2 96
AUC  ------ ⋅ hr
ug
L 
289.4 401 432

AUMC  ------ ⋅ hr 
ug 2
L 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  ------
ug
 L
Vd (L)
Cp at 1 hour  ------
ug
 L
Cpmax  ug
------
 L
Tmax (hr)

Isosorbide Dinitrate (Problem 8 - 9)

Straehl, P. and Galeazzi, R., "Isosorbide dinitrate bioavailability , kinetics, and metabolism", Clinical Pharmacology and Thera-
peutics, Vol. 38m (1985), p. 140 - 149.
Isosorbide dinitrate is used in the treatment of angina pectoris, vasospastic angina, and congestive heart failure.
In this study volunteers received a 5 mg intravenous dose given over 5 minutes and a 10 mg tablet. The different dos-
age forms were separated by a washout period. A summary of the some of data obtained from this experiment is given
below.

Dose (mg/kg) 5 10 10
370.3 158 165
AUC  ug
------ ⋅ hr
L 
487 310 305

AUMC  ug
------ ⋅ hr 
2
L 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  ------
ug
 L
Vd (L)
Cp at 1 hour  ug
------
 L
Cpmax  ------
ug
 L
Tmax (hr)

Ketanserin (Problem 8 - 10)

Kurowski, M., "Bioavailability and pharmacokinetics of ketanserin in elderly subjects", Journal of Clinical Pharmacology, Vol. 28,
(1988), p. 700 - 706.
Ketanserin is a 5-hydroxytryptamine S2-antagonist. This study focuses on the kinetics of Ketanserin in the
elderly. Subjects were given either a 10 mg intravenous dose or a 40 mg oral tablet. A summary of the some of data
obtained from this experiment is given below.

Dose (mg) 10 40 40
247 520 400
AUC  -------- ⋅ hr
ng
 mL 
3991 8922 8922

AUMC  -------- ⋅ hr 
ng 2
 mL 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  --------
ng
 mL
Vd (L)
Cp at 1 hour  --------
ng
 mL
Cpmax  --------
ng
mL
Tmax (hr)

Methotrexate (Problem 8 - 11)

Seideman, P., et al., " The pharmacokinetics of methotrexate and its 7-hydroxy metabolite in patients with rheumatoid arthritis",
British Journal of Clinical Pharmacology, 35 (1993), p. 409 - 412.
The drug Methotrexate is a folic acid which has been shown to inhibit dihydrofolate reductase. The impor-
tance of this drug at present is mostly seen in the area of oncology, but lately it has been used for rheumatoid arthritis.
Methotrexate has a molecular weight of 454.4. In this study, the drug was administered both by IV bolus and orally as
a 15 mg dose. The following data was obtained:

Dose (mg) 15 15 15
2752 2708 2700
AUC  nmole
---------------- ⋅ hr
 L 
15887 18400 18500

AUMC  nmole
---------------- ⋅ hr 
2
 L 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  ----------------
nmole
 L 
Vd (L)
Cp at 1 hour  nmole
----------------
 L 
Cpmax  ----------------
nmole
 L 
Tmax (hr)

Moclobemide (Problem 8 - 12)

Schoerlin, M. et al., "Disposition kinetics of moclobemide, a new MAO-A inhibitor, in subjects with impaired renal function", Jour-
nal of Clinical Pharmacology, Vol. 30 (1991), p. 272 - 284.
Moclobemide is an antidepressant agent that reversibly inhibits the A-isozyme of the monoamine oxidase
enzyme system. In this study, single IV and oral doses were administered to a patient. A summary of the some of data

Dose (mg) 150 100 100
2.58 1.70 1.52
AUC  -------- ⋅ hr
ug
 mL 
6.35 5.91 5.90

AUMC  -------- ⋅ hr 
ug 2
 mL 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  --------
ug
 mL
Vd (L)
Cp at 1 hour  --------
ug
 mL
Cpmax  --------
ug
mL
Tmax (hr)

Nalbuphine (Problem 8 - 13)

Nalbuphine hydrochloride is an agonist-antagonist opiod which is used for its analgesic actions. In this study,
volunteers were given single doses of four different nalbuphine forms. The data below focuses on a 10 mg iv dose and
a 45 mg dose of an oral solution. A summary of the some of data obtained from this experiment is given below.

Dose (mg) 10 45 40 40
86.9 70.3 62.5 60
AUC  -------- ⋅ hr
ng
 mL 
288 306 280 270

AUMC  -------- ⋅ hr 
ng 2
 mL 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  --------
ng
 mL
Vd (L)
Cp at 1 hour  --------
ng
 mL
Cpmax  --------
ng
mL
Tmax (hr)

Nefazodone (Problem 8 - 14)

Shukla, U. et al., "Pharmacokinetics, absolute bioavailability, and disposition of nefazodone in the dog", Drug Metabolism and
Disposition, Vol. 21, No. 3, (1993), p. 502 - 507.
Nefazodone was given to four healthy, adult, male beagles with an average weight of 11.0 kg. Each dog was
given a 10 mg/kg dose as a either a intravenous injection or as an oral solution or tablet. A summary of the some of
data obtained from this experiment is given below.

Dose (mg/kg) 10 10 10 10
6023 829 800 700
AUC  -------- ⋅ hr
ng
 mL 
29283 4875 4800 4500

AUMC  -------- ⋅ hr 
ng 2
 mL 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  --------
ng
 mL
Vd (L)
Cp at 1 hour  --------
ng
 mL
Cpmax  --------
ng
mL
Tmax (hr)

Ondansetron (Problem 8 - 15)

Colthup, P., et al., "Determination of ondansetron in plasma and its pharmacokinetics in the young and elderly", Journal of Phar-
maceutical Sciences, Vol. 80, No. 9(1991), p. 868 - 871.
Ondansetron is a 5-hydroxyltryptamine compound which is useful in treating the nausea and vomiting which is
caused by the use of chemotherapy and radiation in the cancer patients. In order to determine the absolute bioavailabil-
ity of oral Ondansetron, doses of 8 mg were given to two groups. One group received an oral dose and the other group
received an intravenous dose. A summary of the some of data obtained from this experiment is given below.

Dose (mg) 8 8 8
246.5 139 145
AUC  -------- ⋅ hr
ng
 mL 
1138 795 870

AUMC  -------- ⋅ hr 
ng 2
 mL 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  --------
ng
 mL
Vd (L)
Cp at 1 hour  --------
ng
 mL
Cpmax  --------
ng
mL
Tmax (hr)


Anderson, T., et al, "Pharmacokinetics of various single intravenous and oral doses of omeprazole", Eur Journal of Clinical Phar-
macology, 39, (1990), p. 195 - 197.
Omeprazole (mw: 345.42) is an agent which inhibits gastric acid secretion from the parietal cell. It is useful in
treating such problems as ulcers and gastroesophageal reflux disease. One group received an iv bolus dose and the
other group received an oral dose. A summary of the some of data obtained from this experiment is given below.

Dose (mg) 20 40 40
µmole 3.2 3.5 3.0

AUC  ---------------- ⋅ hr
 L 
µmole 3.2 5.25 4.5

AUMC  ---------------- ⋅ hr 
2
 L 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
µmole
Cp0  ----------------
 L 
Vd (L)
µmole
Cp at 1 hour  ----------------
 L 
µmole
Cpmax  ----------------
 L 
Tmax (hr)

Paroxetine (Problem 8 - 17)

Lund, J., et al., "Paroxetine: pharmacokinetics and cardiovascular effects after oral and intravenous single doses in man", Journal
of Pharmacology and Toxicology, Vol. 51, (1982), p. 351 - 357.
Paroxetine kinetics and cardiovascular effects were studied in male subjects after single oral doses of 45 mg
and slow intravenous infusion of 23 - 28 mg. A summary of the some of data obtained from this experiment is given
below.

Dose (mg) 28 45 45
467 750 675
AUC  -------- ⋅ hr
ng
 mL 
6671 11250 10463

AUMC  -------- ⋅ hr 
ng 2
 mL 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  --------
ng
 mL
Vd (L)
Cp at 1 hour  --------
ng
 mL
Cpmax  -------
ng-
 mL
Tmax (hr)

Ranitidine (Problem 8 - 18)

Garg, D., et al., "Pharmacokinetics of ranitidine in patients with renal failure", Journal of Clinical Pharmacology, Vol. 26 (1986),
p. 286 - 291.
Ranitidine is an agent used in the treatment of peptic ulceration. In this study, ten patients with renal failure
received either a 50 mg intravenous bolus dose or a 150 mg tablet. A summary of the some of data obtained from this

Dose (mg) 50 150 150
5159 6422 6753
AUC  -------- ⋅ hr
ng
 mL 
53415 78752 84413

AUMC  -------- ⋅ hr 
ng 2
 mL 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  --------
ng
 mL
Vd (L)
Cp at 1 hour  --------
ng
 mL
Cpmax  --------
ng
mL
Tmax (hr)

Sulpiride (Problem 8 - 19)

Bressolle, F., Bres, J., and Faure-Jeantis, A., "Absolute bioavailability , rate of absorption, and dose proportionality of sulpiride in
humans", Journal of Pharmaceutical Sciences ,Vol. 81, No. 1 (1992), p. 26 - 32.
Sulpiride is a substituted benzamine antipsychotic. In this study, the drug was administered to two groups.
The first group received a 200 mg oral dose and the second group received a 100 mg intravenous infusion. A summary
of the some of data obtained from this experiment is given below.

Dose (mg) 100 200 200 200
8.27 8.79 8.6 8.0
AUC  -------- ⋅ hr
ug
 mL 
79.1 87.3 91.1 84.5

AUMC  -------- ⋅ hr 
ug 2
 mL 
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0  --------
ug
 mL
Vd (L)
Cp at 1 hour  --------
ug
 mL
Cpmax  --------
ug
mL
Tmax (hr)

8.7 Solutions
8.7.1 “CAFFEINE” ON PAGE 61

Aramaki, S., et al., "Pharmacokinetics of caffeine and its metabolites in horses after intravenous, intramuscular, or oral adminis-
tration", Chem Pharm Bull, Vol. 30, No. 11, (1991), p. 2999 - 3002.
This study deals with the pharmacokinetics of caffeine. Caffeine doses of 2.5 mg/kg were administered both intrave-
nously and orally to horses with an average weight of about 500 kg. A summary of the some of data obtained from this
experiment is given below. Fill in the empty cells.
TABLE 8-25 Caffeine

Dose (mg/kg) 2.5 2.5 2.5 2.5
63.1 60.7 60 57
AUC  -------- ⋅ hr
ug
 mL 
1442 1556.8 1600 1723

AUMC  -------- ⋅ hr 
ug 2
 mL 
MRT (hr) 22.9 25.7 26.7 30.2

MAT (hr) 2.79 3.81 7.36
ke (hr-1) 0.0438
ka (hr-1) 0.358 0.262 0.136

2.76
Cp0  --------
ug
 mL
V d (L/kg) 0.91
2.64 0.78 0.59 0.31
Cp at 1 hour  -------
ug-
 mL
f 0.96 0.95 .90

2.76 1.98 1.83 1.45 0.79
Cpmax  --------
ug
 mL
Tmax (hr) 6.69 8.19 12.1 1.5

Relative Bioavailability 0.95
Generic Equivalent (Yes / No) NO

2
⋅ h-
1442ug ---------------
MRT = AUMC mL
1. ------------------ = ---------------------------- = 22.9 hours
AUC 2
⋅ h-
63.1ug ---------------
mL
1 = -------------
1 = 0.044 h – 1
2. k = ------------
MRT 22.9h
ln 2 = 0.693
3. t 1 ⁄ 2 = -------- --------------------- = 15.75h
k –1
0.044h
⋅ h ⋅ 0.0044h – 1 = 2.76 -------
Cp 0 = AUC ⋅ k = 63.1 ug ug-
4. -------------
mL mL
5. The horses have an average weight of 500 kg.
Dose = 2.5 mg
------- ⋅ 500kg = 1250mg
kg
ug- = 2.78 mg
Cp 0 = 2.78 ------- -------
mL L
2.5mg ⁄ kg = 0.91 -----

Vd = Dose 1250mg- = 449.6L = ------------------------- L-
------------- = -------------------
Cp 0 mg mg kg
2.78 ------- 2.78-------
L L
=  2.78 -------
– kt ug- ( e – 0.044 ( 1 ) ) = 2.64 -------
ug-
6. Cp = Cp0 e
mL mL
⋅h
AUC oral Dose iv 60 ug ------------- 2.5 mg -------
mL kg = 0.95
7. f = --------------------- ⋅ ----------------- = -------------------- ⋅ ------------------------
Dose oral AUC iv ⋅h
2.5 mg ------- 63.1ug -------------
kg mL
2
ug ⋅ h -
1556.8 ---------------
= AUMC mL - = 25.7h
8. MRT po ------------------ = --------------------------------
AUC ug ⋅h
60.7-------------
mL
Where AUMC is that which is given for the oral dose.
Where AUC is that which is given for the oral dose.
9. MAT po = MRT po – MRT iv = 25.7h – 22.9h = 2.79h

10.
1 = ---------
k a = ------------ 1 - = 0.358hr – 1
MAT 2.79
 0.358hr – 1
k
ln  -----
a ln  ------------------------
k  0.044h
–1

11. tp = ---------------- = ------------------------------------------------------ = 6.7hr
ka – k –1 –1
0.358hr – 0.044hr
–1
fD ka – ktp katp 0.96 ⋅ 1250mg 0.358hr –( 0.044 ⋅ 6.7 ) – ( 0.358 ⋅ 6.7 )
12. Cp max = ------ ⋅ -------------- ⋅ ( e –e ) = ----------------------------------- ⋅ ------------------------------------------------- ⋅ ( e ⋅e )
V ka – k 449L –1
( 0.358 – 0.044 )hr
generic ( AUC ) ⁄ ( Dose

generic )
-
 57  -------
ug- ⋅ hr  ⁄  2.5 mg -------
  mL    km
CB = ------------------------------------------------------------- = 0.95
 60  -------
ug    mg
  mL- ⋅ hr  ⁄  2.5 ------- km
14. Bioequivalent: Yes if all three = Yes:
0.80 < CB < 1.25 CB = 0.95 = Yes
t p generic t p generic
0.80 < -------------- < 1.25 -------------- = 12.1hr
---------------- = 1.5 = NO
tp brand t pbrand 8.19hr
ug-
C p max –g eneric C p max –g eneric 1.45 -------
mL- = 0.79 = NO
0.80 < -----------------------
- < 1.25 ------------------------ = ------------------
C p max – b rand C p max –b rand ug-
1.83 -------
mL

8.7.2 “CEFETAMET PIVOXIL” ON PAGE 62

Ducharme, M., et. al., "Bioavailability of syrup and tablet formulations of cefetamet pivoxil", Antimicrobial Agents and Chemo-
therapy, Vol. 37, No. 12, (1993), p. 2706 - 2709.
Cefetamet pivoxil is a prodrug of cefetamet. This study compares the bioavailability of cefetamet pivoxil in tablet
form versus syrup form. A summary of the some of data obtained from this experiment is given below. Fill in the
approprate cells.
.

Dose (mg) 250 500 500 500
30.64 53.68 50 47
AUC  -------
ug- ⋅ hr
 mL 
101.66 191.64 205.6 225.3

AUMC  -------
ug- ⋅ hr 2
 mL 
MRT (hr) 3.32 3.57 4.11 4,79

MAT (hr) 0.252 0.794 1.48
ke (hr-1) 0.301
ka (hr-1) 3.97 1.26 0.678

9.23
Cp0  --------
ug
 mL
Vd (L) 27.1
6.83 12.62 9.03 5.91
Cp at 1 hour  -------
ug-
 mL
f 0.88 0.82 0.77

9.23 13.1 9.6 7.4 0.77
Cpmax  --------
ug
 mL
Tmax (hr) 0.70 1.49 2.15 1.44

2
mg ⋅ h
101.66 -----------------
MRT = AUMC L
1. ------------------ = ---------------------------------- = 3.32 hours
AUC 2
mg ⋅ h
30.64 -----------------
L
Where AUMC is that which is given for the intravenous dose.
Where AUC is that which is given for the intravenous dose.

1 1 –1
2. k = ------------ = ------------- = 0.301 h
MRT 3.32h
ln 2 = ---------------------
0.693 = 2.3h
3. t 1 ⁄ 2 = --------
k –1
0.301h
⋅ h- ⋅ 0.301h – 1 = 9.22 mg
4. Cp 0 = AUC ⋅ k = 30.64 mg
-------------- -------
L L
V d = Dose 250mg
5. ------------- = ------------------ = 27.06L
Cp 0 9.24mg -------
L
=  9.24 mg
------- ( e
– 0.301 ( 1 )
) = 6.84mg
– kt
6. Cp = Cp 0 e -------
L L
⋅ h-
AUC oral Dose iv 53.68mg --------------
7.
L - ⋅ ----------------------------
f = --------------------- ⋅ ----------------- = ---------------------------- 250mg - = 0.876
Dose oral AUC iv 500mg ⋅ h-
30.64 mg --------------
L
2
mg ⋅ h
191.64 -----------------
= AUMC L
8. MRT po ------------------ = ---------------------------------- = 3.57h
AUC mg ⋅ h
53.68 ---------------
L
Where AUMC is that which is given for the oral dose.
Where AUC is that which is given for the oral dose.
9. MAT po = MRT po – MRT iv = 3.57h – 3.32h = 0.252hr
1 = ------------
1 - = 3.97hr – 1
10. k a = ------------
MAT 0.252
 4.0h – 1 
k
ln  ----a-
ln  --------------------- 
k  0.301h – 1
11. t p = ---------------- = ------------------------------------------- = 0.7h
ka – k –1 –1
4.0h – 0.301h
–1
12. Cp max = fD ka ⋅ ( e – kt – e –k a t ) = 0.88
------ ⋅ -------------- ( 500mg ) ⋅ ---------------------------------------------
-------------------------------- 3.97hr - ⋅ (e
– 0.301 ( 0.7 )
–e
– 3.97 ( 0.7 )
) = 13.1mg
-------
V ka – k 27.1L –1 L
( 3.97 – 0.301 )hr
generic ( AUC ) ⁄ ( Dose

generic )
-

 47  -------
ug 
  mL- ⋅ hr  ⁄ 500mg
CB = -------------------------------------------------------- = 0.94
 50  -------
ug 
  mL- ⋅ hr  ⁄ 500mg
14. Bioequivalent: Yes if all three = Yes:
0.80 < CB < 1.25 CB = 0.94 = Yes
t p generic t p generic
0.80 < -------------- < 1.25 -------------- = 2.15hr
---------------- = 1.44 = NO
tp brand t pbrand 1.49hr
ug-
C p max –g eneric C p max – g eneric 7.4 -------
0.80 < -----------------------
- < 1.25 mL
------------------------ = ---------------- = 0.77 = NO
C p max – b rand C p max– b rand ug-
9.6 -------
mL

8.7.3 “CEFIXIME” ON PAGE 63

Faulkner, R. ,et al., "Absolute bioavailability of cefixime in man", Journal of Clinical Pharmacology, Vol. 28 (1988), p. 700 - 706.
Cefixime is a broad-spectrum cephalosporin which is active against a variety of gram positive and gram nega-
tive bacteria. In this study, sixteen subjects each received a 200 mg intravenous dose and then a 200 mg capsule with a
washout period between the administration of each dosage form. A summary of the some of data obtained from this

Dose (mg) 200 200 200
47 23.6 20.2
AUC  -------- ⋅ hr
ug
 mL 
183.3 162.8 187.5

AUMC  -------- ⋅ hr 
ug 2
mL
MRT (hr) 3.9 6.9 9.3

MAT (hr) 3.0 5.38
ke (hr-1) 0.256
ka (hr-1) 0.334 0.186

12.1
Cp0  --------
ug
mL
Vd (L) 16.6
9.3 1.5 0.77
Cp at 1 hour  --------
ug
 mL
f 0.50 0.43
12.1 2.5 1.6 0.64
Cpmax  -------
ug-
 mL
Tmax (hr) 3.4 4.6 1.33


8.7.4 “CEFTIBUTEN” ON PAGE 64

"The pharmacokinetics of ceftibuten in humans"
Ceftibuten is a new oral cephalosporin with potent activity against enterobacteriaceae and certain gram posi-
tive organisms. In this study two groups received either a 400 mg oral dosage form of ceftibuten or a 200 mg iv bolus
dose of ceftibuten. A summary of the some of data obtained from this experiment is given below.

Dose (mg) 200 400 400 400
75.2 65.9 64.2 64
AUC  -------
ug- ⋅ hr
 mL 
211.2 213.4 220 208

AUMC  -------
ug- ⋅ hr 2
 mL 
MRT (hr) 2.94 3.24 3.43 3.25

MAT (hr) 0.297 0.485 0.309
ke (hr-1) 0.390
ka (hr-1) 3.37 2.06 3.24

25.6
Cp0  -------
ug-
 mL
Vd (L) 7.8
18.2 16.9 15.3 16.4
Cp at 1 hour  --------
ug
 mL
f 0.44 0.42 0.43

25.6 17.3 15.3 16.7 1.09
Cpmax  --------
ug
 mL
Tmax (hr) 0.76 1.05 0.78 0.74

Relative Bioavailability 1

8.7.5 “CIMETIDINE” ON PAGE 65

Sandborn, W., et al., "Pharmacokinetics and pharmacodynamics of oral and intravenous cimetidine in seriously ill patients", Jour-
nal of Clinical Pharmacology, Vol. 30, (1990), p. 568 - 571.
Cimetidine is a histamine receptor antagonist which is used in the treatment of gastric and duodenal ulcer dis-
ease. In this study, patients received 300 mg of cimetidine as an iv bolus on the first day and data was collected. On
the second day, the patients received 300 mg orally and data was collected. A summary of the some of data obtained

Dose (mg) 300 300 300
3.81 2.48 2.50
AUC  -------
ug- ⋅ hr
 mL 
5.33 11.73 10.73

AUMC  -------
ug- ⋅ hr 2
 mL 
MRT (hr) 1.40 4.73 4.29

MAT (hr) 3.33 2.89
ke (hr-1) 0.715
ka (hr-1) 0.300 0.346

2.72
Cp0  -------
ug-
 mL
Vd (L) 110
1.33 0.32 0.37
Cp at 1 hour  --------
ug
 mL
f 0.65 0.66
2.72 0.40 0.44 1.1
Cpmax  --------
ug
 mL
Tmax (hr) 2.1 2.0 0.94

Relative Bioavailability 1
Generic Equivalent (Yes / No) YES

8.7.6 “DIURNAL VARIABILITY IN THEOPHYLLINE BIOAVAILABILITY”

ON PAGE 66
Bauer, L., Gibaldi, M., and Vestal, R., "Influence of pharmacokinetic diurnal variation on bioavailability estimates", Clinical Phar-
macokinetics, vol. 9, (1984), p. 184 - 187.
This article discusses the effects of diurnal variation on the bioavailability and clearance of theophylline. In
this study patients received a 500 mg dose every 12 hours either orally or by iv bolus. A summary of the some of data
obtained from this experiment for the time period between midnight and noon is given below.

Dose (mg) 500 500 500 500
160.25 144.58 140 144
AUC  -------
ug- ⋅ hr
 mL 
1821 1662 1785 1700

AUMC  -------
ug- ⋅ hr 2
 mL 
MRT (hr) 11.40 11.50 12.75 11.8

MAT (hr) 0.13 1.39 0.44
ke (hr-1) 0.088
ka (hr-1) 7.58 0.721 2.26

14.1
Cp0  -------
ug-
 mL
Vd (L) 35.5
12.9 11.8 6.02 10.7
Cp at 1 hour  --------
ug
 mL
f 0.90 0.87 0.90

14.1 12.1 9.20 11.1 1.21
Cpmax  --------
ug
 mL
Tmax (hr) .059 3.3 1.5 0.45


8.7.7 “CIS-5-FLUORO-1-[2-HYDROXYMETHYL-1,3-OXATHIOLAN-5-YL]
CYTOSINE (FTC)” ON PAGE 67
Frick, L. , et al., "Pharmacokinetics, oral bioavailability, and metabolic disposition in rats of (-)-cis-5-Fluoro-1-[2-Hydroxyme-
thyl-1,3-Oxathiolan-5-yl] Cytosine, a nucleoside analog active against human immunodeficiency virus and hepatitis B virus", Anti-
microbial Agents and Chemotherapy, Vol. 37, No. 11, (1993), p. 2285 - 2292.
FTC is a 2',3'-didoexynucleoside analog that may be useful against HIV and HBV. In this study, rats with an
average weight of 270 g were given either iv or oral doses of 100 mg/kg. A summary of the some of data obtained

Dose (mg/kg) 100 100 100
265 168 175
AUC  -------
ug- ⋅ hr
 mL 
19514 12600 13125

AUMC  -------
ug- ⋅ hr 2
 mL 
MRT (hr) 73.6 75 75

MAT (hr) 1.36 1.36
ke (hr-1) .0136
ka (hr-1) 0.734 0.734

3.6
Cp0  -------
ug-
 mL
Vd (L/kg) 27.7
3.55 1.18 1.23
Cp at 1 hour  --------
ug
 mL
f 0.63 0.66
3.6 2.1 2.2 1.04
Cpmax  --------
ug
 mL
Tmax (hr) 5.54 5.54 1.0


8.7.8 “HYDROMORPHONE” ON PAGE 68

Vallner, J., et al., "Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to
human subjects", Journal of Clinical Pharmacology, Vol. 21, (1981), p. 152 - 156.
Hydromorphone hydrochloride is an analog of morphine which has about seven times the effect of morphine
when given intravenously. In this study, volunteers were given a 2 mg intravenous dose and a 4 mg oral dose of hydro-
morphone on separate days. A summary of the some of data obtained from this experiment is given below.

Dose (mg) 2 4 4
83 87.2 96
AUC  ------ ⋅ hr
ug
L
289.4 401 432
AUMC  ug
------ ⋅ hr 
2
L 
MRT (hr) 3.49 4.60 4.50

MAT (hr) 1.11 1.03
ke (hr-1) 0.287
ka (hr-1) 0.899 0.987

23.8
Cp0  ------
ug
 L
Vd (L) 84
17.9 12.6 14.7
Cp at 1 hour  ug
------
 L
f 0.53 0.56
23.8 14.6 16.6 1.13
Cpmax  ------
ug
 L
Tmax (hr) 1.87 1.77 0.95


8.7.9 “ISOSORBIDE DINITRATE” ON PAGE 69

Straehl, P. and Galeazzi, R., "Isosorbide dinitrate bioavailability , kinetics, and metabolism", Clinical Pharmacology and Thera-
peutics, Vol. 38m (1985), p. 140 - 149.
Isosorbide dinitrate is used in the treatment of angina pectoris, vasospastic angina, and congestive heart failure.
In this study volunteers received a 5 mg intravenous dose and a 10 mg tablet. The different dosage forms were sepa-
rated by a washout period. A summary of the some of data obtained from this experiment is given below.

Dose (mg/kg) 5 10 10
370.3 158 165
AUC  ------ ⋅ hr
ug
L 
487 310 305

AUMC  ------ ⋅ hr 
ug 2
L 
MRT (hr) 1.32 1.96 1.85

MAT (hr) 0.65 0.53
ke (hr-1) 0.760
ka (hr-1) 1.546 1.875

282
Cp0  ug
------
 L
Vd (L) 17.75
132 60.1 66.2
Cp at 1 hour  ------
ug
 L
f 0.21 0.22
282 60.4 67.8 1.12
Cpmax  ------
ug
 L
Tmax (hr) 0.90 0.81 0.90


8.7.10 “KETANSERIN” ON PAGE 70

Kurowski, M., "Bioavailability and pharmacokinetics of ketanserin in elderly subjects", Journal of Clinical Pharmacology, Vol. 28,
(1988), p. 700 - 706.
Ketanserin is a 5-hydroxytryptamine S2-antagonist. This study focuses on the kinetics of Ketanserin in the
elderly. Subjects were given either a 10 mg intravenous dose or a 40 mg oral tablet. A summary of the some of data

Dose (mg) 10 40 40
541 112.5 103.9
AUC  -------
ng- ⋅ hr
 mL 
11700 24900 22900

AUMC  -------
ng- ⋅ hr 2
 mL 
MRT (hr) 21.6 22.1 22.0

MAT (hr) 0.5 0.4
ke (hr-1) 0.0402
ka (hr-1) 2.0 2.5

25.0
Cp0  -------
ng-
 mL
Vd (L) 400
23.9 43.6 42.7
Cp at 1 hour  --------
ng
 mL
f .052 0.48
25.0 47.6 44.5 0.94
Cpmax  --------
ng
 mL
Tmax (hr) 1.93 1.63 0.84


8.7.11 “METHOTREXATE” ON PAGE 71

Seideman, P., et al., " The pharmacokinetics of methotrexate and its 7-hydroxy metabolite in patients with rheumatoid arthritis",
British Journal of Clinical Pharmacology, 35 (1993), p. 409 - 412.
The drug Methotrexate is a folic acid which has been shown to inhibit dihydrofolate reductase. The impor-
tance of this drug at present is mostly seen in the area of oncology, but lately it has been used for rheumatoid arthritis.
Methotrexate has a molecular weight of 454.4. In this study, the drug was administered both by IV bolus and orally as
a 15 mg dose. The following data was obtained:

Dose (mg) 15 15 15
2752 2708 2700
AUC  ---------------- ⋅ hr
nmole
 L 
15887 18400 18500

AUMC  ---------------- ⋅ hr 
nmole 2
L
MRT (hr) 5.77 6.79 6.85

MAT (hr) 1.02 1.08
ke (hr-1) 0.173
ka (hr-1) 0.979 0.927

477
Cp0  ----------------
nmole
L
Vd (L) 69.3
401 265 256
Cp at 1 hour  ----------------
nmole
 L 
f 0.98 0.98
477 323 318 0.98
Cpmax  nmole
----------------
 L 
Tmax (hr) 2.15 2.23 1.04


8.7.12 “MOCLOBEMIDE” ON PAGE 72

Schoerlin, M. et al., "Disposition kinetics of moclobemide, a new MAO-A inhibitor, in subjects with impaired renal function", Jour-
nal of Clinical Pharmacology, Vol. 30 (1991), p. 272 - 284.
Moclobemide is an antidepressant agent that reversibly inhibits the A-isozyme of the monoamine oxidase
enzyme system. In this study, single IV and oral doses were administered to a patient. A summary of the some of data

Dose (mg) 150 100 100
2.58 1.70 1.52
AUC  -------
ug- ⋅ hr
 mL 
6.35 5.91 5.90

AUMC  -------
ug- ⋅ hr 2
 mL 
MRT (hr) 2.46 3.48 3.80

MAT (hr) 1.02 1.42
ke (hr-1) 0.406
ka (hr-1) 0.985 0.704

1.05
Cp0  -------
ug-
 mL
Vd (L) 143
0.698 0.344 0.250
Cp at 1 hour  --------
ug
 mL
f .099 .088
1.05 .037 0.29 .079
Cpmax  --------
ug
 mL
Tmax (hr) 1.53 1.85 1.21


8.7.13 “NALBUPHINE” ON PAGE 73

Nalbuphine hydrochloride is an agonist-antagonist opiod which is used for its analgesic actions. In this study,
volunteers were given single doses of four different nalbuphine forms. The data below focuses on a 10 mg iv dose and
a 45 mg dose of an oral solution. A summary of the some of data obtained from this experiment is given below.

Dose (mg) 10 45 40 40
86.9 70.3 62.5 60
AUC  -------
ng- ⋅ hr
 mL 
288 306 280 270

AUMC  -------
ng- ⋅ hr 2
 mL 
MRT (hr) 3.31 4.35 4.48 4.5

MAT (hr) 1.04 1.17 1.19
ke (hr-1) .0301
ka (hr-1) 0.963 0.858 0.843

26.2
Cp0  -------
ng-
 mL
Vd (L) 381
19.4 11.1 9.2 8.7
Cp at 1 hour  --------
ng
 mL
f 0.180 0.180 0.173

26.2 12.5 10.7 10.2 0.95
Cpmax  --------
ng
 mL
Tmax (hr) 1.76 1.88 1.90 1.01


8.7.14 “NEFAZODONE” ON PAGE 74

Shukla, U. et al., "Pharmacokinetics, absolute bioavailability, and disposition of nefazodone in the dog", Drug Metabolism and
Disposition, Vol. 21, No. 3, (1993), p. 502 - 507.
Nefazodone was given to four healthy, adult, male beagles with an average weight of 11.0 kg. Each dog was
given a 10 mg/kg dose as a either a intravenous injection or as an oral solution or tablet. A summary of the some of
data obtained from this experiment is given below.

Dose (mg/kg) 10 10 10 10
6023 829 800 700
AUC  -------
ng- ⋅ hr
 mL 
29283 4875 4800 4500

AUMC  -------
ng- ⋅ hr 2
 mL 
MRT (hr) 4.86 5.88 6.0 6.43

MAT (hr) 1.02 1.14 1.57
ke (hr-1) 0.210
ka (hr-1) 0.982 0.879 0.638

1238
Cp0  -------
ng-
 mL
Vd (L) 8.07
1009 94.8 85.7 60.7
Cp at 1 hour  --------
ng
 mL
f 0.138 0.133 0.116

1238 112.7 105.6 84.0 0.80
Cpmax  --------
ng
 mL
Tmax (hr) 2.0 2.16 2.62 1.21


8.7.15 “ONDANSETRON” ON PAGE 75

Colthup, P., et al., "Determination of ondansetron in plasma and its pharmacokinetics in the young and elderly", Journal of Phar-
maceutical Sciences, Vol. 80, No. 9(1991), p. 868 - 871.
Ondansetron is a 5-hydroxyltryptamine compound which is useful in treating the nausea and vomiting which is
caused by the use of chemotherapy and radiation in the cancer patients. In order to determine the absolute bioavailabil-
ity of oral Ondansetron, doses of 8 mg were given to two groups. One group received an oral dose and the other group
received an intravenous dose. A summary of the some of data obtained from this experiment is given below.

Dose (mg) 8 8 8
246.5 139 145
AUC  -------
ng- ⋅ hr
 mL 
1138 795 870

AUMC  -------
ng- ⋅ hr 2
 mL 
MRT (hr) 4.62 5.72 6.0

MAT (hr) 1.10 1.38
ke (hr-1) 0.217
ka (hr-1) 0.907 0.723

53.4
Cp0  -------
ng-
 mL
Vd (L) 150
43 15.9 14.7
Cp at 1 hour  --------
ng
 mL
f 0.56 0.59
53.4 19.2 18.8
Cpmax  --------
ng
 mL
Tmax (hr) 2.1 2.4 1.1


8.7.16 “OMEPRAZOLE” ON PAGE 76

Anderson, T., et al, "Pharmacokinetics of various single intravenous and oral doses of omeprazole", Eur Journal of Clinical Phar-
macology, 39, (1990), p. 195 - 197.
Omeprazole (mw: 345.42) is an agent which inhibits gastric acid secretion from the parietal cell. It is useful in
treating such problems as ulcers and gastroesophageal reflux disease. One group received an iv bolus dose and the
other group received an oral dose. A summary of the some of data obtained from this experiment is given below.

Dose (mg) 20 40 40
3.2 3.5 3.0
AUC  µmole
---------------- ⋅ hr
 L 
µmole ⋅ hr 2 3.2 5.25 4.5

AUMC  ----------------
 L 
MRT (hr) 1.0 1.5 1.5

MAT (hr) 0.5 0.5
ke (hr-1) 1
ka (hr-1) 2 2
µmole 3.2
Cp0  ----------------
 L 
Vd (L) 52.4
1.18 1.63 1.40
Cp at 1 hour  µmole
----------------
 L 
f 0.55 0.47
µmole 3.2 1.8 1.5 0.86

Cpmax  ----------------
 L 
Tmax (hr) 0.69 0.69 1


8.7.17 “PAROXETINE” ON PAGE 77

Lund, J., et al., "Paroxetine: pharmacokinetics and cardiovascular effects after oral and intravenous single doses in man", Journal
of Pharmacology and Toxicology, Vol. 51, (1982), p. 351 - 357.
Paroxetine kinetics and cardiovascular effects were studied in male subjects after single oral doses of 45 mg
and slow intravenous infusion of 28 mg. A summary of the some of data obtained from this experiment is given below.

Dose (mg) 28 45 45
467 750 675
AUC  -------- ⋅ hr
ng
 mL 
6671 11250 10463

AUMC  -------- ⋅ hr 
ng 2
 mL 
MRT (hr) 14.3 15 15.5

MAT (hr) 0.72 1.22
ke (hr-1) 0.07
ka (hr-1) 1.40 .082

32.7
Cp0  --------
ng
 mL
Vd (L) 856
30.5 37.9 25.5
Cp at 1 hour  -------
ng-
 mL
f 1 0.90
32.7 44.8 37.6 0.84
Cpmax  --------
ng
 mL
Tmax (hr) 2.25 3.27 1.45


8.7.18 “RANITIDINE” ON PAGE 78

Garg, D., et al., "Pharmacokinetics of ranitidine in patients with renal failure", Journal of Clinical Pharmacology, Vol. 26 (1986),
p. 286 - 291.
Ranitidine is an agent used in the treatment of peptic ulceration. In this study, ten patients with renal failure
received either a 50 mg intravenous bolus dose or a 150 mg tablet. A summary of the some of data obtained from this

Dose (mg) 50 150 150
5159 6422 6753
AUC  -------
ng- ⋅ hr
 mL 
53415 78752 84413

AUMC  -------
ng- ⋅ hr 2
 mL 
MRT (hr) 10.4 12.3 12.5

MAT (hr) 1.91 2.15
ke (hr-1) 0.0966
ka (hr-1) 0.524 0.466

498
Cp0  -------
ng-
 mL
Vd (L) 100
452 240 231
Cp at 1 hour  --------
ng
 mL
f .0415 0.436
498 423 432 1.02
Cpmax  --------
ng
 mL
Tmax (hr) 3.96 4.26 1.07


8.7.19 “SULPIRIDE” ON PAGE 79

Bressolle, F., Bres, J., and Faure-Jeantis, A., "Absolute bioavailability , rate of absorption, and dose proportionality of sulpiride in
humans", Journal of Pharmaceutical Sciences ,Vol. 81, No. 1 (1992), p. 26 - 32.
Sulpiride is a substituted benzamine antipsychotic. In this study, the drug was administered to two groups.
The first group received a 200 mg oral dose and the second group received a 100 mg intravenous infusion. A summary
of the some of data obtained from this experiment is given below.

Dose (mg) 100 200 200 200
8.27 8.79 8.6 8.0
AUC  -------
ug- ⋅ hr
 mL 
79.1 87.3 91.1 84.5

AUMC  -------
ug- ⋅ hr 2
 mL 
MRT (hr) 9.56 9.93 10.6 10.6

MAT (hr) 0.367 1.02 1.0
ke (hr-1) 0.865
ka (hr-1) 2.72 0.972 1.0

0.865
Cp0  -------
ug-
 mL
Vd (L) 116
0.779 0.798 0.526 0.498
Cp at 1 hour  --------
ug
 mL
f 0.53 0.52 0.48

0.865 0.807 0.687 0.643 0.94
Cpmax  --------
ug
 mL
Tmax (hr) 1.24 2.57 2.52 0.98


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CHAPTER 9 Clearance
OBJECTIVES
changes in clearance and other pharmacokinetic parameters inherent in compro-
mised patients.
2. Determine the total clearance based on Dose and AUC.
3. Determine clearance of an organ based on dose, AUC, and fraction of drug elimi-
nated by the organ
4. Determine change in clearance due to functional changes in an organ.
5. Determine change in clearance due to change in blood flow through an organ.
6. Prepare a professional consult (V) and justify (VI) modifications in drug therapy
based on clearance of a drug.

Clearance
9.1 Equations
Rate of Elimination
Cl = --------------------------------------------------- (EQ 9-1)
Serum Concentration
⋅ D os-
Cl tot = f--------------- (EQ 9-2)
AUC
Cl r = Cl tot ⋅ ( Fraction of drug that is renally eliminated ) (EQ 9-3)
Cl H = Cl tot ⋅ ( Fraction of drug that is hepatically eliminated ) (EQ 9-4)
L min L
Q r = 0.0191 -------------------- renal blood perfusion ⋅ 70kg ⋅ 60 --------- ≈ 80 -----blood (EQ 9-5)
min ⋅ kg hr hr
L min L
Q H = 0.0238 -------------------- hepatic blood perfusion ⋅ 70kg ⋅ 60 --------- ≈ 100 -----blood (EQ 9-6)
min ⋅ kg hr hr
Er = ( Cl r ) ⁄ Q r (EQ 9-7)
E H = ( Cl H ) ⁄ Q H (EQ 9-8)
Q ⋅ Cl
f u ⋅ Cl int = ---------------- (EQ 9-9)
Q – Cl
Q ⋅ Cl-
---------------
Q – Cl
Cl int = ---------------- (EQ 9-10)
fu
f u∗ ⋅ Cl∗ int
F i = -------------------------
- (EQ 9-11)
f u ⋅ Cl int
∗
FR = Q
------- (EQ 9-12)
Q
Fi ⋅ FR
F Cl = ----------------------------------------- (EQ 9-13)
F R + Er ( Fi – FR )
Cl∗ tot ∗ ⋅ V∗ Cl∗ H + Cl∗ r

- = k----------------
FCl tot = ------------- = ----------------------------- (EQ 9-14)
Cl tot k⋅V Cl H + Cl r
0.80 ≤ FCl t o t ≤ 1.20 (EQ 9-15)

Clearance
9.2 Definitions and Terms

Clearance: The hypothetical volume of a fluid from which a substance is
totally and irreversibly removed per unit time.
3
Dimensions: L ⁄T
Examples of fluids: blood, serum, plasma, bile, gut contents, CSF.
( Cl ), ( Cl tot )
Systemic or Total Body Clearance: Removal process is elimination
(excretion and metabolism). Fluid is usually plasma or serum (rarely blood).
( Cl r ) Renal Clearance: Removal process is urinary excretion of

unchanged drug. Fluid is usually plasma or serum (rarely blood).
( Cl m ) Metabolic Clearance: Removal process is metabolism. Fluid is usu-

ally blood (rarely plasma or serum).
( Cl H ) Hepatic Clearance: This is Cl m when the liver is the metabolic

organ.
( Cl cr ) Creatinine Clearance: This is Cl r applied to endogenous creatinine.

It is used to monitor renal function, and thus is a valuable parameter for calculating
dosage regimens in elderly patients or those suffering from renal dysfunction. Cre-
atinine t 1 ⁄ 2 = 231min
Value for normal males: 117 ± 20 ml/min
Value for normal females: 108 ± 20 ml/min
Cl inulin Inulin Clearance: This is Cl r for inulin, and yields the glomerular
filtration rate.
Value for normal males: 124.5 ± 9.7 ml/min
Value for normal females: 108.8 ± 13.5 ml/min

Clearance
9.3 Measurement of Creatinine Clearance

The mass of endogenous creatinine excreted into the urine collected over a given
time interval ( ∆t ) is determined. The mean serum creatinine concentration ( Cs )cr
over that interval is calculated from sample determinations; this should be the con-
centration halfway through the interval. In practice, ∆t = 24hr and, as ( C s ) cr is rela-
tively constant, the serum sample is taken at any convenient time.
Let “a” be a volume of serum having a creatinine concentration of ( C s ) cr . The mass

of creatinine in the serum will be a ⋅ ( Cs ) cr . If this creatinine is totally and irrevers-
ibly removed from the serum to the urine in the time interval, ∆t , then
a ⋅ ( C s ) cr = ∆Xu (EQ 9-16)
∆Xu
Thus, a = --------------
- (EQ 9-17)
( C s )cr
The volume of serum from which this creatinine is removed in unit time is a ⁄ ∆t ;
this is the definition of clearance. Hence,
( ∆Xu ⁄ ∆t )
a = --------------------------
T
Cl cr = ----- - (EQ 9-18)
∆t ( C s ) cr
Siersbaek-Neilson et al. report a value of 11.1 µg ⁄ ml for ( Cs )cr in 149 males (aged
20-99). The value of ( ∆X u ⁄ ∆t ) T decreased with age from 16.53 µg ⁄ min per Kg body
weight (age 20-29) to 6.53 µg ⁄ min per Kg body weight (age 90-99). For a 25 year
ml
old 70Kg male, equation 9-18 yields Cl cr = 104.2 ---------
min

Clearance
9.4 Model Correlations

Although intrinsically model independent, clearance can also be related to com-
partmental models.
9.4.1 RENAL CLEARANCE
The plasma renal clearance of a drug may be measured analogously to creatinine

clearance:
( ∆Xu ⁄ ∆t )
Cl r = --------------------------T- (EQ 9-19)
Cp
The practical versions of and states:
( ∆X u ⁄ ∆t ) = k u X = k u VC p (EQ 9-20)
T
Comparing equation 9-19 and equation 9-20,
Cl r = k u V (EQ 9-21)
This relates clearance to model parameters. What is the slope of a plot of ( ∆Xu ⁄ ∆t ) T
against Cp ?
Note that if Cl r > 117 ± 20ml ⁄ min (males), it may indicate active secretion of the drug
into the kidney tubules. If Cl r < 108 ± 20ml ⁄ min (females), it may indicate reabsorp-
tion of the drug from the kidney tubules.
9.4.2 SYSTEMIC CLEARANCE AND METABOLIC CLEARANCE

How could you measure
Cl ? and Cl m
By analogy,
0.693V
Cl tot = KV = ----------------- (EQ 9-22)
t1 ⁄ 2
and K = ku + km , so Cl tot = Cl r + Cl m .
Consequently, fractional changes in clearance,

Clearance
° ° ° °
Cl h + Cl r K ⋅V
F Cl = ------------------------
- = ---------------- (EQ 9-23)
tot Cl h + Cl r K⋅V
where X° is new or altered variable. Hepatic function and renal function are not a
priori connected, although some physiological functional changes might result in
similar changes in clearance of both organs. We can see from equation 9-12 that
changes in total body clearance can result in changes in either K, V, or both. The
consequences of that will be discussed in the section on dosage regimens.
9.4.3 USE IN PHARMACOKINETIC EQUATIONS
Systemic Clearance (Cl) can be used in many equations where the drug is removed
by elimination (renal excretion and metabolism). If renal excretion is the only
removal process, use Cl r l if metabolism, use Cl m . Some examples:
Intravenous infusion: Q-
( C p ) ss = -----
Cl
f( Xa) fD fD
Oral and Intravenous Bolus: Cl = ---------------0 = --------------- = ------------
∞ ∞ AUC
∫ C p dt ∫ C p dt
0 0
This equation becomes a means of calculating Cl from plasma data.
Dosage Regimen: ( Cp ) ss fD -
= ------------
τ ⋅ Cl
These examples are all model-independent expressions, which are very useful in
calculating dosage regimens. The importance of clearance terms rests on their abil-
ity to account for variations in both t 1 ⁄ 2 and / or V simultaneously, as both these
parameters can change in disease states and with age.

Clearance
9.5 Physiological Factors Affecting Clearance
9.5.1 INTRINSIC CLEARANCE ( Cl int )

Intuitively, it may be recognized that two factors will affect the clearance of a
drug:
1. The rate at which blood is presented to the eliminating organ.
2. The intrinsic ability of the eliminating organ to clear the drug.
Mathematically, a hyperbolic equation has been derived to illustrate the relative

effect of these factors. (Note: this is one model of clearance. There are several oth-
ers which also illustrate the effect of these factors.)
Liver Drug Metabolism
QH ⋅ f u ⋅ ( Cl H )int
Cl H = ------------------------------------------ (EQ 9-24)
Q H + f u ⋅ ( Cl H )int
Where Q H is the rate of blood flow through the liver (assumed 23.8 ml/min/Kg
body weight in normal adult),
fu is the fraction unbound of the drug, and
( Cl H ) int is the intrinsic hepatic clearance of the drug.
If there were no physiological limits to the rate of blood flow( Q H → ∞ ), hence equa-
tion 9-24 becomes
Cl H = ( Cl H )int (EQ 9-25)
This equation provides a definition for intrinsic clearance, namely the clearance of
a drug were there to be no physiological limits on the rate of blood flow through
the clearing organ.

Clearance
Kidney drug excretion By analogy for excretion of unchanged drug by the kidney:
Q r ⋅ f u ⋅ ( Cl r )int
Cl r = --------------------------------------- (EQ 9-26)
Q r + fu ⋅ ( Cl r )int
Where Q r is the rate of blood flow through the kidney (assumed 19.1 ml/min per
Kg body weight in normal adults), and
( Cl r ) int is the intrinsic renal clearance of the drug.
Note that the value of Cl cr (assumed 1.75 ml.min per Kg body weight in normal
adults) is about 9% of Q r .
9.5.2 EXTRACTION RATIO (E)

This is defined as “the ratio of the clearance of a drug compared to the rate of
blood flow through the clearing organ.” As such, it indicates what fraction of the
drug in the blood is cleared (extracted) on each passage through the clearing organ.
Note: when using clearance to calculate extraction ratio, blood flow must be used.
Drug metabolism by the

liver
Cl
E H = --------H- (EQ 9-27)
QH
Where EH is the steady-state hepatic extraction ratio.
By comparison with equation 9-24,
f u ⋅ ( Cl H ) int
E H = ------------------------------------------ (EQ 9-28)
Q H + f u ⋅ ( Cl H ) int
Thus, the range of values of E H is from zero, when ( Cl H )int = 0 , to one, when
Q H = 0 or ( Cl H ) int » Q H . For example, propanolol has E H = 0.75 , yielding
17.9ml 71.4ml
Cl H = ----------------------------------------------------- and ( Cl H )int = ----------------------------------------------------- in normal adult males.
min ⋅ Kg body weight min ⋅ Kg body weight

Clearance
Kidney excretion of
unchanged drug
Cl
Er = --------r (EQ 9-29)
Qr
f u ⋅ ( Cl r ) int
Er = --------------------------------------- (EQ 9-30)
Q r + f u ⋅ ( Cl r ) int
where Er is the steady-state renal extraction ratio.
Thus the range of values is from zero, when ( Cl r ) int = 0 , to one, when Qr = 0 or
( Cl r ) int » Q r . For example, digoxin has E r = 0.09 , yielding 1.72ml

Cl r = ----------------------------------------------------
-
min ⋅ Kg body weight
1.89ml
and ( Cl r ) int = ----------------------------------------------------- in normal adult males. In this case, note that
min ⋅ Kg body weight
Cl r ≈ Cl c r

Clearance
9.6 Hepatic Function and Clearance
9.6.1 ALTERATIONS IN HEPATIC BLOOD FLOW

For a given drug, equation 9-24 predicts that alterations in the hepatic blood perfu-
sion rate will cause a change in drug clearance, assuming the intrinsic hepatic
clearance is unaltered. A general equation may be derived relating the ratio of
hepatic clearances at two blood perfusion rates to the fractional change in perfu-
sion rate and the extraction ratio of the drug.
Cl∗ FR
-----------H- = ----------------------------------------
- (EQ 9-31)
Cl H F R + EH ( 1 – F R )
where Cl H denotes normal hepatic clearance,
Cl ∗ H denotes altered hepatic clearance
Q H∗
F R = ---------- is the new flow rate over the old flow rate, the fractional change in blood
QH
perfusion rate, and
EH is the hepatic extraction ratio under normal conditions.
The equation predicts that, for any given decrease in blood perfusion rate, drugs
having a large normal extraction ratio will experience a proportionally greater
reduction in clearance than drugs having a small normal extraction ratio.
Liver blood flow can be reduced by congestive heart failure, for example. The
intrinsic hepatic clearance can be represented by the inherent activity of the
enzymes responsible for drug metabolism.
9.6.2 ALTERATIONS IN HEPATIC INTRINSIC CLEARANCE

For any given drug, equation 9-24 predicts that alterations in the intrinsic hepatic
clearance will cause a change in drug clearance, assuming the blood flow rate is
unchanged. A general equation may be derived relating the ratio of hepatic clear-
ance at two intrinsic hepatic clearances to the fractional change in intrinsic hepatic
and the extraction ratio of the drug.

Clearance
Cl∗ Fi
-----------H- = ----------------------------------- (EQ 9-32)
Cl H 1 + EH ( F i – 1 )
f u∗ ⋅ ( Cl int )∗
where F i = ------------------------------- is the fractional change in fraction unbound times the frac-
f u ⋅ ( Cl int )
tional change in intrinsic hepatic clearance.
The equation predicts that, for any given decrease in intrinsic hepatic clearance,
drugs having a small normal extraction ratio will experience a proportionately
greater reduction in clearance than drugs having a large normal extraction ratio.
The intrinsic hepatic clearance of a drug can be reduced by cirrhosis or increased

by enzyme inducers, such as phenobarbitol.
9.6.3 TABULATED OR GRAPHICAL ALTERATIONS

A table or graph of clearance changes when the hepatic blood flow (but not the
intrinsic hepatic clearance) is altered shows that drugs having a low extraction
ratio ( EH = 0.1 ) need little adjustment in dosage. Even if the hepatic blood flow
were halved ( FR = 0.5 ) , the hepatic clearance is still 91% of its normal value. Con-
versely, dosage adjustment is necessary for drugs having a high extraction ratio
and predominantly eliminated by hepatic metabolism (e.g., propanolol).
A table or graph of clearance changes when the intrinsic hepatic clearance (but not
the hepatic blood flow) is altered shows that drugs having a high extraction ratio
( E H = 0.9 ) need little adjustment in dosage. Even if the intrinsic hepatic clearance
were halved ( Fi = 0.5 ) , the hepatic clearance is still 91% of its normal value. Con-
versely, dosage adjustment is necessary for drugs having a low extraction ratio and
predominately eliminated by hepatic metabolism (e.g., phenylbutazone).

Clearance
9.7 Renal Function and Clearance

Approximately 25% of cardiac output goes to the kidneys or approximately 735
ml/min of plasma is presented to the kidneys of a 70 kg man (19.1 mL/min/kg x 70
kg). Approximately 125 ml/min (1.8 mL/min/kg) of that goes to the glomeruli for
filtration (Glomerular Filtration Rate, GFR). Unbound drug is filtered into the
proximal renal tubule at this point. The remaining plasma (as blood) is shunted
around the tubule in the arterioles adjascent to the proximal tubule where drug
may be actively secreted from the arteriol into the proximal tubule or actively
reabsorbed in the opposite direction. As the blood flows down the vessels adjas-
cent to the loop of Henle, the drug may be also passively reabsorbed into the blood
vessel as the water in the urine is being reabsorbed and the urine is being concen-
trated.
This leads to some interesting possibilities:
1. Cl r = f u ⋅ GFR . It is likely that the drug is filtered only, in this case, . It is also possible that
secretion and reabsortion balance and cancel each orther out but are still occurring. The actual
clearance of the drug may be low as the drug may be bound to plasma protiens or red blood
cells.
11. Cl r > f u ⋅ GFR . Net active secretion is infered in this case. These active mechanisms are non-
specific and consequently, drugs actively secreted compete with each other. Secretion, if it
occurs, occurs on the unbound drug and thus is also effected by changes in free fraction. In
cases where secretion is very rapid and as a consequence, virtually all of the drug is removed by
the single pass through the kidney (Er ~1), the disssociation of the drug from the protien or out
of the red blood cells is not a hinderance. Some reabsorption may occur but it is less than secre-
tion.
12. Cl r < f u ⋅ GFR . Net active reabsorbtion is infered in this case. Active reabsorption occurs for
many exogenous compounds, including glucose and vitamins. For many compounds, reabsorp-
tion is passive, occurring only as a consequence of the concentration gradient produced as water
is removed from the urine as is proceeds down the renal tubule. Since the membrane is lipoidal
in nature, polar compounds, ionized acids and ionized bases are less likely to be reabsorbed.
Thus changing the pH of the urine would result in changing the reabsorption characteristics of
weakly acidic or basic drugs.
For low molecular weight drugs (<2,000 dalton) , filtration always occurs. Active
secretion, active reabsorption and passive reabsorption may occur.
It has been found that renal blood flow is little affected by changes in blood flow
elsewhere. However, in chronic renal dysfunction there are two effects which
exhibit a parallel decline. One is a decrease in glomerular filtration rate (GFR), as
measured by Cl cr , and the other is the net secretion of drugs into the kidney
tubules. Note that p-amino hippurate (PAH) clearance measures the sum of both
effects.

Clearance
For any given drug, equation 9-26 predicts that alterations in both the renal blood
perfusion rate (as manifest by the GFR) and the intrinsic renal clearance will cause
a change in drug clearance. A general equation may be derived relating the ratio of
renal clearances at two different blood flow rates and two different intrinsic renal
clearances.
Cl∗
-----------r = F i (EQ 9-33)
Cl r
where F i is the fractional change in drug unbound times the fractional change in
intrinsic renal clearance.
In this case,
f u∗
-⋅F
F i = ------ (EQ 9-34)
fu R
where FR is the fractional change in blood flow rate (or GFR).
Thus, equation 9-33 shows that the renal clearance of a drug is reduced by a con-
stant fraction, independent of the renal extraction ratio ( E r ) . This fractional
decrease can be estimated by changes in creatinine clearance:
Cl∗ cr
FR = ------------
- (EQ 9-35)
Cl cr
where Cl∗ cr is the altered creatinine clearance
Substituting, equation 9-33 through equation 9-35, we get:
Cl∗ r Cl ∗ cr
----------- = ------------
- (EQ 9-36)
Cl r Cl cr
This equation shows why, in cases of chronic renal dysfunction, a change in the
measured creatinine clearance indicated a likely change in drug renal clearance.
Hence, dosage adjustments are made on this basis, particularly for drugs predomi-
nantly eliminated by renal filtration (e.g., gentamicin, digoxin).

Clearance
9.8 General Equations for Changes in Clearance

For each clearing organ,
Cl ° FI ⋅ FR
F Cl = ------ = ---------------------------------------
- (EQ 9-37)
Cl F R + E ( F I – FR )
When a drug has a high extraction ratio, E ≈ 1 , then equation 9-26 becomes
F Cl ≈ F R (EQ 9-38)
and when a drug has a low extraction ratio, E ≈ 0 , then equation 9-26 becomes
F Cl ≈ F I (EQ 9-39)
Thus, the clearance of drugs with a high extraction ratio are more effected by phys-
iological changes in flow of blood to the clearing organ, while drugs with a low
extraction ratio are more effected by physiological changes in the function of the
organ.
9.8.1 PLASMA/BLOOD RATIO

Calculation of Extraction Ratio requires measurement in whole blood by defini-
tion. Since most clinical measurements are done in plasma, knowledge of the
plasma/blood ratio is necessary. Blood in made up of plasma and red blood cells
(RBCs). Thus the amount of drug in the blood is made up of the amount of drug in
the plasma and the amount of drug in the RBCs.
C b ⋅ Vb = C p ⋅ Vp + C rbc ⋅ V rbc (EQ 9-40)
where C x ⋅ V x = AMOUNT x
and b = blood, p = plasma, rbc = red blood cell
If we define the ratio of the concentration of the drug in the RBCs to the concentra-
tion of the free drug in plasma as
C rbc
ρ = --------------
- (EQ 9-41)
fu ⋅ C p
and
V rbc = H ⋅ V b (EQ 9-42)

Clearance
Vp = ( 1 – H) ⋅ Vb (EQ 9-43)
Pluging equation 9-41 thru equation 9-43 into equation 9-40 results in:
Cb ⋅ Vb = ( 1 – H ) ⋅ V b ⋅ Cp + f u ⋅ ρ ⋅ H ⋅ Vb ⋅ Cp (EQ 9-44)
Rearranging and simplifying results in:
Cb
------ = 1 + H ⋅ ( fu ⋅ ρ – 1 ) (EQ 9-45)
Cp
H – 1 + ( Cb ⁄ C p )
ρ = ----------------------------------------- (EQ 9-46)
fu ⋅ H
Thus equation 9-46 determines the affinity of the drug for the RBCs. Drugs with a
high affinity for the RBCs should result in a smaller volume of distribution.
For drugs that are primarily filtered by the glomeruli, the renal extraction ratio is:
GFR ⋅ f u ⋅ C p
Rate of filtration - = -------------------------------
E rf = ----------------------------------------------- - (EQ 9-47)
Rate of presentation Qr ⋅ Cb
Putting equation 9-45 into equation 9-47 results in:
GFR ⋅ f u
E rf = ----------------------------------------------------------- (EQ 9-48)
Q r ⋅ ( 1 + H ⋅ ( fu ⋅ ρ – 1 ) )
Thus:
Cl
1. If the the ratio of --------r to calculated Erf from equation 9-48 is one, it is likely that the drug is
Qr
filtered only.
Cl
13. If the the ratio of --------r to calculated Erf from equation 9-48 is greater than one, active secretion
Qr
is infered in this case.
Cl
14. If the the ratio of --------r to calculated Erf from equation 9-48 is less than one, active reabsorb-
Qr
tion is infered in this case.

Clearance
9.8.2 HALF LIFE AND ELIMINATION RATE CONSTANT IN RELATIONSHIP

TO CLEARANCE
The elimination rate constant is related to the volume of distribution and the total
body clearance by equation 9-22 above which when rewritten yields:
Rate of Elimination ( Mass ) ⁄ ( Time ) Cl ( Volume ) ⁄ ( Time )

K = ------------------------------------------------ = ---------------------------------------- = ------ = ---------------------------------------------- (EQ 9-49)
Amount in the body Mass V Volume
Cl Cl pw
K = Cl
------ = -------b- = -------------u (EQ 9-50)
V Vb Vpw u
where b = blood and pwu = unbound plasma water. Clearance of drug from blood
(Clb) is useful in considering drug extraction in the eliminating organs. Volume
and clearance terms based on unbound drug concentration are particularly useful
in therapeutics, because only the unbound drug is thought to cause the therapeutic
action.
9.8.3 EFFECTS OF ALTERATIONS IN PROTEIN BINDING ON CLEARANCE
Protein binding of drugs may be altered in disease states and by interferance bind-
ing by other drugs on the protein. These changes in binding effect Fi , the frac-
tional change in intrinsic clearance in both renal and hepatic clearances even
though the actual intrinsic clearance, the indicator of organ function, may be unef-
fected as shown in equation 9-11:
f u∗ ⋅ Cl ∗int
F i = -------------------------
-
f u ⋅ Cl int
where Cl∗int = Cl int . Thus, a change in protein binding will cause a proportional
change in Fi of both clearances. There is more discussion in the chapter on protein
binding.

Clearance
9.9 Problems
For each of the problems, do questions A through R now and S through W after
completing chapter 10. In doing questions S through W, please try to obtain a
ss
plasma concentration of free drug within 120 % of normal Cp and 80 % of
max free
ss
Cp .
min free

Clearance
Acebutolol (Problem 9 - 1)
Piquette-Miller, M., et. al., “Effect of aging on the pharmacokinetics of acebutolol enantiomers”, Journal of Clinical Pharmacol-
ogy, Vol. 32, (1992), p. 148 - 156. Kukes, VG; Gneushev ET; Mamedov TS; Gneusheva IA; “Acebutolol and diacetolol: thier bind-
ing to plasma and erythrocytes and secretion with saliva.” Farmakol-Toksikol. 1991 Jan-Feb; 54(1)
Acebutolol is a beta-adrenergic blocking agent which is often used in the treatment of hypertension.(Use Qr = 72 L/hr;
PROBLEM TABLE 9 - 1. Acebutolol
Patient Condition Normal Normal FRR=0.5 FIR=0.5 FRH=0.5 FIH=0.5

A Dose(mg) 200 400
B f 0.4
C fu 0.867
D ρ 1.93
E Vd (L)
F k (hr-1)
G T 1/2 (hr) 5.5
H %Clr 40
I %Clnr 60
J AUC (mg/L*hr) 3.97
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr) 12
T N
U ss µg 
Cp  -------
-
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 
Qh = 90 L/hr)

Clearance
TABLE 9 - 1. Answers for Acebutolol

A Dose(mg) 200 400 BID 400 BID 400 BID 400 BID 200 QID
FRR 1 1 0.5 1 1 1
FIR 1 1 0.5 0.5 1 1
FRH 1 1 1 1 0.5 1
FIH 1 1 1 1 1 0.5
B f 0.4
C fu 0.867
D ρ 1.93
E Vd (L) 160
F k (hr-1) 0.126 0.101 0.102 0.12 0.091
G T 1/2 (hr) 5.5 6.87 6.77 5.89 7.64
H %Clr 40 25 26.1 42.9 55.5
I %Clnr 60 75 73.9 57.1 44.6
J AUC (mg/L*hr) 3.97 9.93 9.78 8.51 5.5
K Cl tot (L/hr) 20.2 16.1 16.4 18.8 14.5
L Cl h (L/hr) 12.1 12.1 12.1 10.7 6.5
M Cl r (L/hr) 8.1 4.03 4.27 8.1 8.1
L Eh 0.126
O Er 0.112
P Cl h (L/hr) 16
int
Q Cl r (L/hr) 10.5
int
R FCL 1 0.8 0.81 0.93 0.72
S τ (hr) 12 12 12 12 6
T N 2.18 1.75 1.77 2.04 0.785

U ss µg- 1.11 1.24 1.23 1.15 1.03
Cp  -------
max free  mL
V ss µg- 0.57 0.72 0.71 0.61 0.80

Cp  -------
avg free  mL 
W ss  µg  0.25 0.37 0.36 0.28 0.6

Cp --------
min free  mL 

Clearance
Bisoprolol (Problem 9 - 2)
Kirch, W., et. al., “Pharmacokinetics of bisoprolol during repeated oral administration to healthy volunteers and patients with kid-
ney or liver disease”, Clinical Pharmacokinetics, Vol. 13, (1987), p. 110 - 117.
Bisoprolol (comes as 5 and 10 mg tablets) is a - selective adrenergic antagonist. It is used in the treatment of hyperten-
sion and angina pectoris.(Use Qr = 72 L/hr; Qh = 90 L/hr)
PROBLEM TABLE 9 - 2. Bisoprolol
A Dose(mg) 10 10 TID
B f 0.7
C fu 1
D ρ 1
E Vd (L)
F k (hr-1)
G T 1/2 (hr) 10
H %Clr 50
I %Clnr 50
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg 
Cp  -------
-
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss µg-
Cp  -------
min free  mL 

Clearance
TABLE 9 - 2. Answers for Bisoprolol

A Dose(mg) 10 10 10 10 10 10
FRR 1 1 0.5 1 1 1
FIR 1 1 0.5 0.5 1 1
FRH 1 1 1 1 0.5 1
FIH 1 1 1 1 1 0.5
B f 0.9
C fu 0.7
D ρ
E Vd (L) 152.8
F k (hr-1) 0.0693 0.052 0.0526 0.067 0.0525
G T 1/2 (hr) 10 13.3 13.2 10.3 13.2
H %Clr 50 33.3 34 51.3 66
I %Clnr 50 66.7 66 48.7 34
J AUC (mg/L*hr) 0.661 0.85 0.87 0.69 0.87
K Cl tot (L/hr) 10.6 7.94 8.0 10.3 8.0
L Cl h (L/hr) 5.3 5.3 5.3 5.0 2.7
M Cl r (L/hr) 5.3 2.65 2.8 5.3 5.3
L Eh 0.055
O Er 0.074
P Cl h (L/hr) 5.6
int
Q Cl r (L/hr) 5.7
int
R FCL 1 0.75 0.76 0.97 0.76
S τ (hr) 8 12 12 8 12
T N 0.8 0.9 0.9 0.78 0.91

U ss  µg  0.108 0.099 0.098 0.11 0.098
Cp --------
max free  mL
V ss µg  0.083 0.073 0.073 0.085 0.073

Cp  -------
avg free  mL-
W ss µg  0.062 0.052 0.052 0.064 0.052

Cp  -------
-
min free  mL 

Clearance
Cefonicid (Problem 9 - 3)
Fillastre, J., et. al., “Pharmacokinetics of cefonicid in uraemic patients”, Journal of Antimicrobial Chemotherapy, Vol. 18, (1986),
p. 203 - 211.
Cefonicid is a beta-lactamase resistant cephalosporin which is useful in treating many infections caused by Gram-posi-
tive and Gram-negative organisms. Cefonicid is 80% renally excreted.(Use Qr = 72 L/hr; Qh = 90 L/hr)
PROBLEM TABLE 9 - 3. Cefonicid
B f 1
C fu 0.06
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr) 5.3
H %Clr 80
I %Clnr 20
J AUC (mg/L*hr) 654
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg 
Cp  -------
-
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss µg-
Cp  -------
min free  mL 

Clearance
TABLE 9 - 3. Answers for Cefonicid

A Dose(mg) 1000 1000 1000 1000 1000 1000
FRR 1 1 0.5 1 1 1
FIR 1 1 0.5 0.5 1 1
FRH 1 1 1 1 0.5 1
FIH 1 1 1 1 1 0.5
B f 1
C fu 0.06
D ρ
E Vd (L) 11.7
F k (hr-1) 0.131 0.078 0.079 0.131 0.118
G T 1/2 (hr) 5.3 8.8 8.8 5.3 5.9
H %Clr 80 66.7 66.9 80 88.9
I %Clnr 20 33.3 33.1 20 11.1
J AUC (mg/L*hr) 654 1090 1083 654 727
K Cl tot (L/hr) 1.53 0.917 0.93 1.5 1.4
L Cl h (L/hr) 0.3 0.31 0.31 0.3 0.15
M Cl r (L/hr) 1.22 0.612 0.62 1.22 1.22
L Eh 0.0032
O Er 0.017
P Cl h (L/hr) 5.11
int
Q Cl r (L/hr) 20.7
int
R FCL 1 0.6 0.6 1 0.9
S τ (hr) 8 12 12 8 8
T N 1.51 1.4 1.4 1.51 1.36

U ss µg- 7.9 8.4 8.4 7.9 8.4
Cp  -------
max free  mL
V ss µg- 4.9 5.5 5.4 4.9 5.4

Cp  -------
avg free  mL 
W ss  µg  2.8 3.3 3.3 2.8 3.3

Cp --------
min free  mL 

Clearance
Cefpirome (Problem 9 - 4)
Lameire, N., et. al., “Single-dose pharmacokinetics of cefpirome in patients with renal impairment”, Clinical Pharmacology and
Therapeutics, Vol. 52, (1992), p. 24 - 30.
Cefpirome is a third-generation, broad-spectrum cephalosporin which is useful against many cephalosporin-resistant
organisms.
PROBLEM TABLE 9 - 4. Cefpirome
A Dose(mg) 2000 IV 2000 TID
B f 1
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr) 2.6
H %Clr 85
I %Clnr 15
J AUC (mg/L*hr) 342
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg 
Cp  -------
-
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss µg-
Cp  -------
min free  mL 

Clearance
TABLE 9 - 4. Answers for Cefpirome

A Dose(mg)
B f
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg-
Cp  -------
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
Cefprozil (Problem 9 - 5)
Shyu, W., et. al., “Pharmacokinetics of cefprozil in healthy subjects and patients with renal impairment”, Journal of Clinical Phar-
macology, Vol. 31, (1991), p. 362 - 371.
Cefprozil is a broad-spectrum oral cephalosporin.
PROBLEM TABLE 9 - 5. Cefprozil
A Dose(mg) 1000
B f 0.95
C fu 0.7
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr) 1.2
H %Clr 75
I %Clnr 25
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss  µg 
Cp --------
max free  mL
V ss µg 
Cp  -------
-
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
TABLE 9 - 5. Answers for Cefprozil

A Dose(mg)
B f
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg-
Cp  -------
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
Chloramphenicol (Problem 9 - 6)
Ambrose, P., “Clinical pharmacokinetics of chloramphenicol and chloramphenicol succinate”, Clinical Pharmacokinetics, Vol. 9,
(1984), p. 222 - 238.
Chloramphenicol succinate is a prodrug which is converted in vivo to the active form, chloramphenicol.
PROBLEM TABLE 9 - 6. Chloramphenicol
A Dose(mg) 1000
B f 1
C fu 0.4
D ρ
E Vd (L/kg) 2.8
F k (hr-1)
G T 1/2 (hr) 0.6
H %Clr 30
I %Clnr 70
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss  µg 
Cp --------
max free  mL
V ss µg 
Cp  -------
-
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
TABLE 9 - 6. Answers for Chloramphenicol

A Dose(mg)
B f
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg-
Cp  -------
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
Enalapril (Problem 9 - 7)
Ohnishi, A., et. al., “Kinetics and dynamics of enalapril in patients with liver cirrhosis”, Clinical Pharmacology and Therapeutics,
Vol. 45, (1989), p. 657 - 665.
Enalapril is an ACE inhibitor which is a prodrug that is metabolized in the liver to the active metabolite, enalaprilat.
PROBLEM TABLE 9 - 7. Enalapril
A Dose(mg) 10 mg po 10 BID1
B f 0.65
C fu 0.55
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr) 0.63
H %Clr 27
I %Clnr 73
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss  µg 
Cp --------
max free  mL
V ss µg 
Cp  -------
-
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
TABLE 9 - 7. Answers for Enalapril

A Dose(mg)
B f
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg-
Cp  -------
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
Enoxacin (Problem 9 - 8)
Somogyi, A., and Bochner, F., “The absorption and disposition of enoxacin in healthy subjects”, Journal of Clinical Pharmacol-
ogy, Vol. 28, (1988), p. 707 - 713.
Enoxacin is a fluorinated quinolone which is used to treat infections caused by gram-negative organisms and
Pseudomonoas aeruginosa.
PROBLEM TABLE 9 - 8. Enoxacin
A Dose(mg) 400 200 bid
B f 0.9
C fu 0.8
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr) 7.75
H %Clr 60
I %Clnr 40
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr) 12
T N
U ss µg 
Cp  -------
-
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss µg-
Cp  -------
min free  mL 

Clearance
TABLE 9 - 8. Answers for Enoxacin

A Dose(mg)
B f
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg-
Cp  -------
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
Enprofylline (Problem 9 - 9)
Nadai, M., et. al, “Dose-dependent pharmacokinetics of enprofylline and its renal handling in rats”, Journal of Pharmaceutical
Sciences, Vol. 80, No. 7, (1991), p. 648 - 651
Enprogylline is a xanthine bronchodilator which is more potent than theophylline.
PROBLEM TABLE 9 - 9. Enprofylline
A Dose(mg/kg) 2.5 2.5 TID
B f 1
C fu 0.4
D ρ
E Vd (L/kg)
F k (hr-1)
G T 1/2 (hr) 0.36
H %Clr 90
I %Clnr 10
J AUC (mg/L*hr) 3.6
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss  µg 
Cp --------
max free  mL
V ss µg 
Cp  -------
-
avg free  mL 
W ss  µg 
Cp --------
min free  mL 
TABLE 9 - 9. Answers for Enprofylline

Clearance

A Dose(mg)
B f
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg-
Cp  -------
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
Erythromycin (Problem 9 - 10)

Welling and Creig (JPS 67, 1057-9,1978).
Erythromycin is a macrolide antibiotic.(Use Qr = 72 L/hr; Qh = 90 L/hr)
PROBLEM TABLE 9 - 10. Erythromycin
B f .8
C fu 0.06 0.06 0.12 0.06 0.18
D ρ
E Vd (L) 57 57 100 57 150
F k (hr-1)
G T 1/2 (hr)
H %Clr 10
I %Clnr 90
J AUC (mg/L*hr)
K Cl tot (L/hr) 16.5
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr) 8
T N
U ss  µg 
Cp --------
max free  mL
V ss µg 
Cp  -------
-
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
TABLE 9 - 10. Answers for Erythromycin

A Dose(mg) 300 300 300 200 300 200
FRR 1 1 0.5 1 1 1
FIR 1 1 0.5 0.5 1 3
FRH 1 1 1 1 0.5 1
FIH 1 1 1 2 1 0.5
B f .8
C fu 0.06 0.06 0.12 0.06 0.18
D ρ
E Vd (L) 57 57 100 57 150
F k (hr-1) 0.255 0.242 0.235 0.227 0.075
G T 1/2 (hr) 2.71 2.85 2.92 3.05 9.27
H %Clr 10 5.3 3.1 11.2 37
I %Clnr 90 94.7 96.9 88.8 63
J AUC (mg/L*hr) 14.5 17.4 6.7 18.5 14.2
K Cl tot (L/hr) 16.5 13.8 23.7 13.0 11
L Cl h (L/hr) 13.1 13.1 23.4 11.5 7.02
M Cl r (L/hr) 1.45 0.73 0.73 1.45 4.19
L Eh 0.136
O Er 0.020
P Cl h (L/hr) 252
int
Q Cl r (L/hr) 24.7
int
R FCL 1 0.95 1.63 0.89 0.77
S τ (hr) 8 8 8 8 24
T N 2.94 2.79 2.74 2.63 2.59

U ss µg- 0.29 0.30 0.23 0.30 0.23
Cp  -------
max free  mL
V ss µg- 0.12 0.13 0.10 0.14 0.11

Cp  -------
avg free  mL 
W ss  µg  0.038 0.042 0.034 0.049 0.038

Cp --------
min free  mL 

Clearance
Fleroxacin (Problem 9 - 11)

Singlas, E., et. al., “Disposition of fleroxacind, a new trifluoroquinolone, and its metabolites - pharmacokinetics in renal failure
and influence of haemodialysis”, Clinical Pharmacokinetics, Vol. 19, No. 1, (1990), p. 67 - 79.
Fleroxacin is a trifluorinated quinolone with activity against a variety of gram-negative and gram-positive organisms.
PROBLEM TABLE 9 - 11. Fleroxacin
A Dose(mg) 400 200 tid
B f 0.95
C fu 0.5
D ρ 1.45
E Vd (L)
F k (hr-1)
G T 1/2 (hr) 14
H %Clr 65
I %Clnr 35
J AUC (mg/L*hr) 92
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss  µg 
Cp --------
max free  mL
V ss µg 
Cp  -------
-
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
TABLE 9 - 11. Answers for Fleroxacin

A Dose(mg)
B f
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg-
Cp  -------
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
Fosinopril (Problem 9 - 12)

Hui, K., et. al., “Pharmacokinetics of fosinopril in patients with various degrees of renal function”, Journal of Clinical Pharmacol-
ogy and Therapeutics, Vol. 49, No. 4, (1991), p. 457 - 466.
Fosinopril is an angiotensin converting enzyme inhibitor which is a prodrug that is metabolized to active form, fosino-
prilat.
PROBLEM TABLE 9 - 12. Fosinopril
A Dose(mg) 7.5 IV 20 po qd
B f 1 (Oral
0.36)
C fu 0.01
E Vd (L)
F k (hr-1)
G T 1/2 (hr) 7
H %Clr 0
I %Clnr 100
J AUC (mg/L*hr) 5.1
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr) 24
T N
U ss µg 
Cp  -------
-
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss µg 
Cp  -------
-
min free  mL 

Clearance
TABLE 9 - 12. Answers for Fosinopril

A Dose(mg)
B f
C fu
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss  µg 
Cp --------
max free  mL
V ss µg-
Cp  -------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
Glutathione (Problem 9 - 13)

Mulders, T., et. al., “Characterization of glutathione conjugation in humans: stereoselectivity in plasma elimination pharmacoki-
netics and urinary excretion of (R)- and (S)-2-bromoisovalerylurea in healthy volunteers”, Clinical Pharmacology and Therapeu-
tics, Vol. 53, (1993), p. 49 - 58.
This study explored the pharmacokinetics of glutathione.
PROBLEM TABLE 9 - 13. Glutathione
B f 1
C fu 1
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr) 4.4
H %Clr 35
I %Clnr 65
J AUC (mg/L*hr) 276
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss  µg 
Cp --------
max free  mL
V ss µg 
Cp  -------
-
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
TABLE 9 - 13. Answers for Glutathione

A Dose(mg)
B f
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg-
Cp  -------
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
Guanadrel (Problem 9 - 14)

Halstenson, C., et. al., “Disposition of guanadrel in subjects with normal and impaired renal function”, Journal of Clinical Phar-
macology, Vol. 29, (1989), p. 128 - 132.
Guanadrel is adrenergic blocker used in the treatment of hypertension.
PROBLEM TABLE 9 - 14. Guanadrel
A Dose(mg) 25 mg po 25 BID
B f 1
C fu 0.8
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr) 3.7
H %Clr 40
I %Clnr 60
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr) 12
T N
U ss  µg 
Cp --------
max free  mL
V ss µg 
Cp  -------
-
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
TABLE 9 - 14. Answers for Guanadrel

A Dose(mg)
B f
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg-
Cp  -------
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
Monoxidine (Problem 9 - 15)

Kirch, W., Hutt, H., and Plänitz, V., “The influence of renal function on clinical pharmacokinetics of monoxidine”, Clinical Phar-
macokinetics, Vol. 15, (1988), p. 245 - 253.
Monoxidine is a centrally acting antihypertensive agent which stimulates α 2 -adrenergic receptors.
PROBLEM TABLE 9 - 15. Monoxidine
A Dose(mg) 0.25 IV 0.25 tid
B f 1
C fu 1
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr) 2.75
H %Clr 95
I %Clnr 5
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss  µg 
Cp --------
max free  mL
V ss µg 
Cp  -------
-
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
TABLE 9 - 15. Answers for Monoxidine

A Dose(mg)
B f
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg-
Cp  -------
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
Nalmefene (Problem 9 - 16)

Dixon, R., et. al., “Nalmefence: safety and kinetics after single and multiple oral doses of a new opiod antagonist”, Journal of
Clinical Pharmacology, Vol. 27, (1987), p. 233 - 239.
Nalmefene is a pure opiod antagonist which is currently being investigated for use.
PROBLEM TABLE 9 - 16. Nalmefene
A Dose(mg) 20 IV
B f 0.6 oral
C fu 1
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr) 9.8
H %Clr 70
I %Clnr 30
J AUC (mg/L*hr) 0.3
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss  µg 
Cp --------
max free  mL
V ss µg 
Cp  -------
-
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
TABLE 9 - 16. Answers for Nalmefene

A Dose(mg)
B f
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg-
Cp  -------
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
Nitrendipine (Problem 9 - 17)

Dylewicz, P, et. al, “Bioavailability and elimination of nitrendipine in liver disease”, European Journal of Clinical Pharmacology,
Vol, 32, (1987), p. 563 - 568.
Nitrendipine is a calcium antagonist
PROBLEM TABLE 9 - 17. Nitrendipine
A Dose(mg) 5 IV 25 po BID
B f 1 (oral 0.2)
C fu 0.05
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr) 11.7
H %Clr 0.1
I %Clnr 99.9
J AUC (mg/L*hr)
K Cl tot (L/hr) 90
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss  µg 
Cp --------
max free  mL
V ss µg 
Cp  -------
-
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
TABLE 9 - 17. Answers for Nitrendipine

A Dose(mg)
B f
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg-
Cp  -------
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
Ofloxacin (Problem 9 - 18)

Lamerire, N., et. al., “Ofloxacin pharmacokinetics in chronic renal failure and dialysis”, Clinical Pharmacokinetics, Vol. 21, No.
4, (1995), p. 357 - 371.
PROBLEM TABLE 9 - 18. Ofloxacin

A Dose(mg) 300 300
B f 0.93
C fu 0.74
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr) 6
H %Clr 97
I %Clnr 3
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr) 12
T N
U ss  µg 
Cp --------
max free  mL
V ss µg 
Cp  -------
-
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
TABLE 9 - 18. Answers for Ofloxacin

A Dose(mg)
B f
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg-
Cp  -------
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance

(Use Qr = 72 L/hr; Qh = 90 L/hr)
PROBLEM TABLE 9 - 19. Omeprazole
A Dose(mg) 10 10 BID
B f 0.5 0.75
C fu 0.04 0.06 0.08
D ρ
E Vd (L) 30
F k (hr-1)
G T 1/2 (hr) 2
H %Clr 0
I %Clnr 100
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr) 12
T N
U ss  µg 
Cp --------
max free  mL
V ss µg 
Cp  -------
-
avg free  mL 
W ss  µg 
Cp --------
min free  mL 
TABLE 9 - 19. Answers for Omeprazole
A Dose(mg) 10 10 10 5 10 5

Clearance
FRR 1 1 0.5 1 1 1
FIR 1 1 0.5 0.5 1 2
FRH 1 1 1 1 0.5 1
FIH 1 1 1 1.5 1 0.5
B f 0.5 0.75
C fu 0.04 0.06 0.08
D ρ
E Vd (L) 30
F k (hr-1) 0.347 0.347 0.493 0.31 0.184
G T 1/2 (hr) 2 2 1.41 2.2 3.8
H %Clr 0
I %Clnr 100
J AUC (mg/L*hr) 0.48 0.48 0.338 0.53 0.68
K Cl tot (L/hr) 10.4 10.4 14.8 9.38 5.5
L Cl h (L/hr) 10.4 10.4 14.8 9.38 5.5
M Cl r (L/hr) 0 0 0 0 0
L Eh 0.108
O Er 0
P Cl h (L/hr) 291.5
int
Q Cl r (L/hr) 0
int
R FCL 1 1 1.42 0.90 0.53
S τ (hr) 6 6 8 6 12
T N 3 3 2.83 2.71 3.2

U ss  µg  0.0076 0.0076 0.0051 0.0079 0.011
Cp --------
max free  mL
V ss µg- 0.0032 0.0032 0.0025 0.0035 0.0045

Cp  -------
avg free  mL 
W ss µg  0.00095 0.00095 0.00099 0.0012 0.0012

Cp  -------
-
min free  mL 

Clearance
Piperacillin (Problem 9 - 20)

Johnson, C., et. al., “Single-dose pharmacokinetics of piperacillin and tazobactam in patients with renal disease”, Clinical Phar-
macology and Therapeutics, Vol. 51, (1992), p. 32 - 41.
Piperacillin is a beta-lactam antibiotic.
PROBLEM TABLE 9 - 20. Piperacillin
A Dose(mg) 3000 2000 qid
B f 1
C fu 0.82
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr) 0.95
H %Clr 75
I %Clnr 25
J AUC (mg/L*hr) 276
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr) 6
T N
U ss  µg 
Cp --------
max free  mL
V ss µg 
Cp  -------
-
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
TABLE 9 - 20. Answers for Piperacillin

A Dose(mg)
B f
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg-
Cp  -------
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
Piroxicam (Problem 9 - 21)

Boudinot, S., Funderburg, E., and Boudinot, F., “Effects of age on the pharmacokinetics of piroxicam in rats”, Journal of Pharma-
ceutical Sciences, Vol. 82, No. 3, (1993), p. 254 - 257.
Piroxicam is a nonsteroidal anti-inflammatory drug (NSAID) commonly used in the treatment of arthritis.
PROBLEM TABLE 9 - 21. Piroxicam
A Dose(mg) 70 20 qd
B f 1
C fu 0.007
D ρ
E Vd (L) 9
F k (hr-1)
G T 1/2 (hr) 50
H %Clr 5
I %Clnr 95
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss  µg 
Cp --------
max free  mL
V ss µg 
Cp  -------
-
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
TABLE 9 - 21. Answers for Piroxicam

A Dose(mg)
B f
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg-
Cp  -------
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
Quinidine (Problem 9 - 22)

Quinidine sulfate is used to treat ventricular and supraventricular arrythmias and is available in 200 and 300 mg tablets.
It is known to bind to α -acid glycoprotein (AAG), which is an acute phase reactant. AAG rises in trauma, inflamation,
malignancy and stress and falls in hepatic disease, nephrotic syndrome and malneurtrition for example.(Use Qr = 72 L/
hr; Qh = 90 L/hr)
PROBLEM TABLE 9 - 22. Quinidine
A Dose(mg/kg) 10 10 TID
B f 0.7
C fu 0.2 0.10 0.25 0.15 0.3
D s 0.83
E Vd (L/kg) 2.6 2.0 2.75 2.2 3.0
F k (hr-1)
G T 1/2 (hr) 6.4
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr/kg)
L Cl h (L/hr/kg) 0.20
M Cl r (L/hr/kg) 0.056
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr) 8
T N
U ss µg- MTC
Cp  -------
max free  mL 1.7
V ss  µg 
Cp --------
avg free  mL 
W ss µg  MEC
Cp  -------
-
min free  mL  0.37

Clearance
TABLE 9 - 22. Answers for Quinidine

A Dose(mg) 10 10 10 10 10 5
FRR 1 1 0.5 1 1 1
FIR 1 1 0.25 0.5 0.75 1.5
FRH 1 1 1 1 0.5 1
FIH 1 1 0.5 1.25 0.75 0.5
B f 0.7
C fu 0.20 0.10 0.25 0.15 0.30
D s 0.83
E Vd (L) 2.6 2.0 2.75 2.2 3.0
F k (hr-1) 0.098 0.057 0.101 0.087 0.061
G T 1/2 (hr) 7 12.1 6.9 7.9 11.3
H %Clr 22 12.3 10 22 46
I %Clnr 78 87.7 90 78 54
J AUC (mg/L*hr) 27.3 61.3 20.6 36.5 19.0
K Cl tot (L/hr) 0.256 0.114 0.28 0.19 0.18
L Cl h (L/hr) 0.20 0.10 0.25 0.15 0.1
M Cl r (L/hr) 0.056 0.014 0.028 0.04 0.08
L Eh 0.0021
O Er 0.00078
P Cl h (L/hr) 1.0
int
Q Cl r (L/hr) 0.28
int
R FCL 1 0.45 1.1 0.75 0.72
S τ (hr) 8 8 8 8 8
T N 1.3 0.66 1.16 1.0 0.71

U ss µg  MTC 0.82 0.79 0.95 0.79 0.75
Cp  -------
-
max free  mL 1.7
V ss µg  0.57 0.63 0.65 0.56 0.59

Cp  -------
-
avg free  mL 
W ss µg  MEC 0.37 0.5 0.44 0.39 0.46

Cp  -------
-
min free  mL  0.3

Clearance
Tazobactam (Problem 9 - 23)

Johnson, C., et. al., “Single-dose pharmacokinetics of piperacillin and tazobactam in patients with renal disease”, Clinical Phar-
macology and Therapeutics, Vol. 51, (1992), p. 32 - 41.
Tazobactam is an irreversible beta-lactamase inhibitor.
PROBLEM TABLE 9 - 23. Tazobactam
A Dose(mg) 375 IV 375 qid
B f 1
C fu 0.96
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr) 0.89
H %Clr 68
I %Clnr 32
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr) 6
T N
U ss  µg 
Cp --------
max free  mL
V ss µg 
Cp  -------
-
avg free  mL 
W ss  µg 
Cp --------
min free  mL 
TABLE 9 - 23. Answers for Tazobactam

Clearance

A Dose(mg)
B f
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg-
Cp  -------
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
Theophylline (Problem 9 - 24)

Wagner, J., “Theophylline - pooled Michaelis-Menten parameters and implications”, Clinical Pharmacokinetics, Vol. 10, (1985),
p. 432 - 442.
PROBLEM TABLE 9 - 24. Theophylline
A Dose(mg)
B f
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg 
Cp  -------
-
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
TABLE 9 - 24. Answers for Theophylline

A Dose(mg)
B f
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg-
Cp  -------
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
Tolrestat (Problem 9 - 25)

Troy, S., et. al., “The effect of renal disease on tolrestat pharmacokinetics”, Clinical Pharmacology and Therapeutics, Vol. 51,
(1992), p. 271 - 277.
Tolrestat is an aldose reductase inhibitor used in the treatment of diabetic neuropathy, diabetic nephropathy, and dia-
betic retinopathy. (Use Qr = 72 L/hr; Qh = 90 L/hr)
PROBLEM TABLE 9 - 25. Tolrestat
B f 0.8
C fu
D ρ
E Vd (L)
F k (hr-1)
G T 1/2 (hr) 10.6
H %Clr 25
I %Clnr 40 bile 35 metab.
J AUC (mg/L*hr) 86
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss µg 
Cp  -------
-
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss µg-
Cp  -------
min free  mL 

Clearance
TABLE 9 - 25. Answers for Tolrestat

A Dose(mg) 200 200 TID 200 TID 200 TID 200 TID 200 BID
FRR 1 1 0.5 1 1 1
FIR 1 1 0.5 0.5 1 1
FRH 1 1 1 1 0.5 1
FIH 1 1 1 1 1 0.5
B f 0.8
C fu 1
E Vd (L) 28.5
F k (hr-1) 0.0654 0.057 0.057 0.065 0.041
G T 1/2 (hr) 10.6 12.1 12.1 10.7 16.9
H %Clr 25 14.3 14.3 25.3 39.8
I %Clnr 75 85.7 85.7 74.7 60.2
J AUC (mg/L*hr) 86 98.3 98.2 87 137
K Cl tot (L/hr) 1.86 1.63 1.63 1.84 1.17
L Cl h (L/hr) 1.4 1.4 1.4 1.4 0.7
M Cl r (L/hr) 0.46 0.23 0.47 0.47 0.47
L Eh 0.0155
O Er 0.0065
P Cl h (L/hr) 1.42
int
Q Cl r (L/hr) 0.47
int
R FCL 1 0.88 0.88 0.99 0.63
S τ (hr) 8 8 8 8 12
T N 0.75 0.66 0.66 0.75 0.71

U ss µg- 13.8 15.3 15.3 13.9 14.4
Cp  -------
max free  mL
V ss µg- 10.8 12.3 12.3 10.9 11.4

Cp  -------
avg free  mL 
W ss µg  8.2 9.6 9.7 8.3 8.8

Cp  -------
-
min free  mL 

Clearance
Vancomycin (Problem 9 - 26)

Macais, W., Meuller, B., and Scarim, S., “Vancomycin pharmacokinetics in acute renal failure; preservation of nonrenal clear-
ance”, Clinical Pharmacology and Therapeutics, Vol., 50, (1991), p. 688 - 694.
Vancomycin is a glycopeptide antibiotic used in the treatment of infections caused by Gram-positive organisms.
PROBLEM TABLE 9 - 26. Vancomycin
A Dose(mg) 1000 500 QID
B f 1
C fu
D ρ 0.44
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr 70
I %Clnr 30
J AUC (mg/L*hr) 543
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss  µg 
Cp --------
max free  mL
V ss µg 
Cp  -------
-
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
TABLE 9 - 26. Answers for Vancomycin

A Dose(mg)
B f
C fu
E Vd (L)
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr)
M Cl r (L/hr)
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss  µg 
Cp --------
max free  mL
V ss µg-
Cp  -------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
Xipamide (Problem 9 - 27)

Knauf, H, et. al., “Xipamide disposition in liver cirrhosis”, Clinical Pharmacology and Therapeutics, Vol. 48, No. 6, (1990), p. 328
- 632.
Xipamide is a diuretic that has been used in the treatment of congestive heart failure, hypertension, advanced renal fail-
ure, and hepatic edema.(Use Qr = 72 L/hr; Qh = 90 L/hr)
PROBLEM TABLE 9 - 27. Xipamide
A Dose(mg) 40 40 QID
B f 0.8
C fu 0.01 0.01 0.02 0.01 0.025
E Vd (L) 21
F k (hr-1)
G T 1/2 (hr)
H %Clr
I %Clnr
J AUC (mg/L*hr)
K Cl tot (L/hr)
L Cl h (L/hr) 1.38
M Cl r (L/hr) 0.72
L Eh
O Er
P Cl h (L/hr)
int
Q Cl r (L/hr)
int
R FCL 1
S τ (hr)
T N
U ss  µg 
Cp --------
max free  mL
V ss  µg 
Cp --------
avg free  mL 
W ss  µg 
Cp --------
min free  mL 

Clearance
TABLE 9 - 27. Answers for Xipamide

A Dose(mg) 40 40 QID 40 QID 20 QID 40 QID 20 QID
FRR 1 1 0.5 1 1 1
FIR 1 1 0.5 0.5 1 2.5
FRH 1 1 1 1 0.5 1
FIH 1 1 1 2 1 0.5
B f 0.8
C fu 0.01 0.01 0.02 0.01 0.025
E Vd (L) 21
F k (hr-1) 0.1 0.083 0.146 0.1 0.118
G T 1/2 (hr) 6.9 8.4 4.7 7.0 5.9
H %Clr 34 21 12 35 72
I %Clnr 66 79 88 65 28
J AUC (mg/L*hr) 15.2 18.4 7.8 15.4 6.5
K Cl tot (L/hr) 2.1 1.74 3.1 2.1 2.5
L Cl h (L/hr) 1.38 1.38 2.71 1.36 0.7
M Cl r (L/hr) 0.72 0.36 0.36 0.72 1.8
L Eh 0.0144
O Er 0.01
P Cl h (L/hr) 140
int
Q Cl r (L/hr) 73
int
R FCL 1 0.83 1.46 1 1.18
S τ (hr) 6 6 4 6 6
T N 0.87 0.71 0.847 0.86 1

U ss  µg  0.034 0.039 0.034 0.034 0.038
Cp --------
max free  mL
V ss µg- 0.025 0.031 0.026 0.025 0.027

Cp  -------
avg free  mL 
W ss µg  0.019 0.024 0.019 0.019 0.019

Cp  -------
-
min free  mL 

CHAPTER 10 Dosage Regimen (Healthy,
Aged, and Diseased Patients)

OBJECTIVES
1. Given population average patient data, the student will devise (V) dosage regi-
mens which will maintain plasma concentrations of drug within the therapeutic
range.
2. Given specific patient information, the patient will justify (VI) dosage regimen
recommendations.
3. Given patient information regarding organ function, the student will devise (V)
and justify (VI) dosage regimen recommendations for the compromised patient.
4. The student will write (V) a professional consult using the above calculations

Dosage Regimen (Healthy, Aged, and Diseased Patients)
10.1 Therapeutic Drug Monitoring
10.1.1 THERAPEUTIC RANGE
The pharmacokinetics of a drug determine the blood concentration achieved from

a prescribed dosing regimen. During multiple drug dosing, the blood concentration
will reflect the drug concentration at the receptor site; and it is the receptor site
concentration that determines the intensity of the drug’s effect. Therefore, in order
to predict a patient’s response to a drug regimen, both the pharmacokinetics and
pharmacological response characteristics of the drug must be understood.
There exists a fundamental relationship between drug pharmacokinetics and phar-

macologic response. The relationship between response and ln-concentration is
sigmoidal. A threshold concentration of drug must be attained befor any response
is ellicited at all. Therapy is accheived when the desired effect is attained because
the required concentration has been reached. That concentration would set the
lower limit of utility of the drug, and is called Effective Concentration (MEC).
Most drugs are not “clean”, that is exhibit only the desired therapeutic response.
They also exhibit undesired side effects, sometimes called toxic effects at a higher,
hopefully a lot higher, concentration. At some concentration, these toxic side
effects become become intollerable. That concentration, or one below it, would
set the upper limit of utility for the drug and is called the Maximum Therapeutic
Concentration or Minimum Toxic Concentration (MTC). Patient studies have
generated upper (MTC) and lower (MEC) plasma concentration ranges that are
deemed safe and effective in treating specific disease states. These concentrations
are known as the “therapeutic range” for the drug (see Table 10-1).When a drug is
administered at a fixed dosage to numerous subjects, the blood concentrations
achieved vary greatly due to biological variation. However it is possible to have a
reasomable
Clinically, digoxin concentrations below 0.8 ng ⁄ ml will elicit a subtherapeutic

effect. Alternatively, when the digoxin concentration exceeds 2.0 ng ⁄ ml side
effects occur (nausea and vomiting, abdominal pain, visual disturbances). Drugs
like digoxin possess a narrow therapeutic index because the concentrations that

may produce toxic effects are close to those required for therapeutic effects. The
importance of considering both pharmacokinetics and pharmacodynamics is clear.
TABLE 10-1. Average therapeutic drug concentration
DRUG RANGE
digoxin 0.8-2.0 ng ⁄ ml
gentamicin 2-10 µg ⁄ ml l
lidocaine 1-4 µg ⁄ ml
lithium 0.4-1.4 mEq ⁄ L
phenytoin 10-20 µg ⁄ ml
phenobarbitol 10-30 µg ⁄ ml
procainamide 4-8 µg ⁄ ml
quinidine 3-6 µg ⁄ ml
theophylline 10-20 µg ⁄ ml
Note that drug concentrations may be expressed by a variety of units.
Pharmacokinetic factors that cause variability in plasma drug concentration are:

• Drug-drug interaction
• patient disease state
• physiological states such as age, weight, sex
• drug absorption variation
• differences in the ability of a patient to metabolize and eliminate the drug
If we were to give an identical dose of drug to a large group of patients and then
measure the highest plasma drug concentration we would see that due to individual
variability, the resulting plasma drug concentrations differ. This variability can be
attributed to factors influencing drug absorption, distribution, metabolism, and
excretion. Therefore, drug dosage regimens must take into account any disease
altering state or physiological difference in the individual.
Therapeutic drug monitoring optimizes a patient’s drug therapy by determining

plasma drug concentrations to ensure the rapid and safe drug level in the therapeu-
tic range.

Two components make • Assays for determination of the drug concentration in plasma
up the process of • Interpretation and application of the resulting concentration data to develop a safe and effective
therapeutic drug drug regimen.
monitoring:
The major potential advantages of therapeutic drug monitoring are the maximiza-
tion of therapeutic drug benefits and the minimization of toxic drug effects. The
formulation of drug therapy regimens by therapeutic drug monitoring involves a
process for reaching dosage decisions.
10.1.2 THERAPEUTIC MONITORING: WHY DO WE CARE?

The usefulness of a drug’s concentration vs. time profile i based on the observation
that for many drugs there is a relationship between plasma concentration and ther-
apeutic response. There is a drug concentration below which the drug is ineffec-
tive, the Minimum Effective Concentration (MEC), and above which the drug has
untoward effects, the Minimum Toxic Concentration (MTC). That defines the
range in which we must attempt to keep the drug concentration (Therapeutic
Range).
The data in Table 10-1 are population averages. Most people respond to drug con-
centrations in these ranges. There is always the possibility that the range will be
different in an individual patient.
For every pharmacokinetic parameter that we measure, there is a population aver-

age and a range. This is normal and is called biological variation. People are differ-
ent. In addition to biological variation there is always error in the laboratory assays
that we use to measure the parameters and error in the time we take the sample.
Even with these errors, in many cases, he therapy is better when we attempt to
monitor the patient’s plasma concentration to optimize therapy than if we don’t.
This is called therapeutic monitoring. If done properly, the plasma concentrations
are rapidly attained and maintained within the therapeutic range throughout the
course of therapy. This is not to say all drugs should be monitored. Some drugs
have a such a wide therapeutic range or little to no toxic effects that the concentra-
tions matter very little. Therapeutic monitoring is useful when:
• a correlation exists between response and concentration
• the drug has a narrow therapeutic range
• the pharmacological response is not easily assessed
• there is a wide inter-subject range in plasma concentrations for a given dose
In this era of DRGs, where reimbursement is no longer tied to cost, therapeutic

monitoring of key drugs can be economically beneficial to an institution. A recent
study (DeStache 1990) showed a significant difference with regard to days in the

hospital between the patients on gentamicin who were monitored (and their dosage
regulated as a consequence) vs. those who were not. With DRGs the hospital was
reimbursed a flat fee irrespective of the number of days the patient stayed in the
hospital. If the number of days cost less than what the DRG paid, the hospital
makes money. If the days cost more than the hospital loses money. This study
showed that if all patients in the hospital who were on gentamicin were monitored,
the hospital would save $4,000,000. That’s right FOUR MILLION per year. I
would say that would pay my salary, with a little left over, and that is only one
drug!
The process of • First the MD must order the blood assays.
therapeutic monitoring • Second, someone (nurse, med tech, you) must take the blood.
takes effort.
• Someone (lab tech, you) must assay the drug concentration in the blood.
• You must interpret the data
• You must communicate your interpretation and your recommendations for dosage regimen
change to the MD. This will allow for informed dosage decisions.
• You must follow through to ensure proper changes have been made.
• You must continue the process throughout therapy. Therapeutic monitoring, in many cases, will
be part of your practice. It can be very rewarding
Thus, if we have deterimined the therapeutic range, we could use pharmacokinet-

ics to determine the optimum dosage regemin to maintain the patient’s plasma con-
centration within that range.
10.1.3 STEADY STATE
It is rare that a drug is given only once. Most therapies consist of multiple doses
of several days duration, if not several years. It is necessary, therefore, to be able
to asess plasma concenterations, both the peak which much be at or below the
MTC and the trough which must be at or above the MEC for the drug to be effec-
tive under these conditions. Thus when we dose a patient, the concentration pro-
file must be within the Therapeutic Range during the entire time that the patient is
taking the drug. We can calculate the plasma concentrations in the followin man-
ner. In the simplest model, suppose we give a drug by IV Bolus (because the math
is simpler). The equation which would result be
=  ---- ⋅ e
( –kt ) D ( – kt)
I.V. Bolus Multiple Dose Cp = Cp 0 ⋅ e (EQ 10-1)
V 
The peak would be

1 D (EQ 10-2)
Cp max = ----
V
If we allowed the drug to be eliminated for τ hours, the trough would be:
1 D ( –( k ⋅ τ ) )
Cp min = ---- ⋅ e (EQ 10-3)
V
Upon giving a second dose, prior to the complete removal by the body of the first
dose the Cp max 2 would be the second dose plus what was left from the first dose:
D ( – ( k ⋅ τ ) )
Cp max = ---- +  ---- ⋅ e
2 D
(EQ 10-4)
V V 
2 2 ( –(k ⋅ τ ))
and the Cp min would be Cp max times e , thus:
( –( k ⋅ τ ) )  D ( –( 2k ⋅ τ ) )
: Cp min = D
2
---- ⋅ e + ---- ⋅ e (EQ 10-5)
V  V 
n
After n doses, the Cp max would be:
(–( k ⋅ τ) ) ( – ( ( n – 1 )k ⋅ τ ) )
Cp max = D
---- + D +…+D
n
---- ⋅ e ---- ⋅ e (EQ 10-6)
V V V
n
while the Cp min would be:
(–( k ⋅ τ) )  D ( – ( 2k ⋅ τ ) ) ( – ( nk ⋅ τ ) )
Cp min = D +…+D
n
---- ⋅ e + ---- ⋅ e ---- ⋅ e (EQ 10-7)
V V  V
Subtracting equation 10-7 from equation 10-6 to eliminate the series yields:
Cp max – Cp min = ---- –  ---- ⋅ e

n n D D ( – ( nk ⋅ τ )) D – ( nk ⋅ τ )
--- ⋅ ( 1 – e
 = -V ) (EQ 10-8)
V V
n n –( k ⋅ τ )
Cp min is also Cp max ⋅ e which means that
n n n n –( k ⋅ τ ) n –( k ⋅ τ )
Cp max – Cp min = Cp max – Cp max ⋅ e = Cp max ( 1 – e ) (EQ 10-9)
n
Equating equation 10-8 and equation 10-9 and solving for Cp max yields:
–( nk ⋅ τ )
Cp max = D
---- ⋅ 1----------------------------
–e
n
(EQ 10-10)
V 1 – e–(k ⋅ τ )
At large n, e – ( nk ⋅ τ ) ⇒ 0 and thus the steady state maximum, Cp max

ss
, is:

= D 1
ss
Cp max ---- ⋅ ------------------------- (EQ 10-11)
V 1 – e–( k ⋅ τ )
ss
and the steady state minimum, Cp min , is :
–( k ⋅ τ )
ss D e
Cp min = ---- ⋅ ------------------------- (EQ 10-12)
V 1 – e –( k ⋅ τ )
In order to make a general equation set from equation 10-11 and equation 10-12,
τ
let N be the number of half lives in a dosing interval, N = --------- , and
t1 ⁄ 2
N
= 1---
–(k ⋅ τ ) –( k ⋅ τ )
k = ( ln ( 2 ) ) ⁄ t 1 ⁄ 2 . Substituting into the function e , yields e and
 2
thus equation 10-11 becomes:
= D 1 -
ss
Cp max ---- ⋅ -------------------- (EQ 10-13)
V 1 N
1 –  ---
 2
and equation 10-12 becomes :

N
 1---
ss D  2
Cp min = ---- ⋅ --------------------- (EQ 10-14)
V 1 N
1 –  ---
 2
The average drug concentration under these conditions would be equivalant to the
steady state concentration attained by an infusion of the same rate, i.e. if we were
to give a multiple dose at 200 mg every four hours (q4h) or 400 mg every eight
hours (q8h), the average that would be attained would be equivelaent to the steady
state plasma concentration attained by giving an infusion at 50 mg/hr, (Q = 50 mg/
ss Q D
hr), and thus, in the infusion, the Cp = ---------- and in multiple dosing Q = ---- , and
k⋅V τ
k ⋅ τ = 0.693 ⋅ N so:
ss D D 1.443 ⋅ D
Cp = ------------------- = ------------------------------ = ---------------------- (EQ 10-15)
avg V ⋅ K ⋅ τ V ⋅ 0.693 ⋅ N N⋅V
Oral Multiple Dosing Similar equations, although more complex, can be derived for multiple dose oral
(Approximation) products. However, if we were agreed to live with some error these equations, with
some modifications could be used to approximate multiple dose oral products.
The error on both calculated Cp maxss and Cp minss would be in the direction of
safety, i.e. the calculated Cp maxss would be higher and the calculated Cp minss would
be lower that their respective multiple dose oral calculations. Thus, if the simpler

equations place the Cp max ss and C minss within the Therapeutic Range, the oral multi-
ple dose equations would also. The two modifications would be to the Dose. Bio-
availability, f, must be considered, and if the drug given is not the drug measured in
the blood, the salt factor, S, the difference in the molecular weight of the two com-
MW measured
pounds must be taken into account, (i.e. S = ------------------------------
- ). Thus, when amino-
MW given
phyline, which is a complex consisting of two theophyline molecules and an
ethylinedyamine molecule is given, but theophyline is measured, the salt factor,
MW Theo 2 ⋅ 180.17
S = -----------------------
- = ------------------------ = 0.857 . Thus for oral multiple dose, we can approximate
MW Amino 420.44
for
using IV bolus equations as such :
ss S⋅f⋅D 1
Cp max = ------------------ ⋅ --------------------- (EQ 10-16)
V N
1 –  1--- 
 2
ss S⋅f⋅D S⋅f⋅D 1.443 ⋅ S ⋅ f ⋅ D

Cp = ------------------- = ------------------------------ = ------------------------------------ (EQ 10-17)
avg V ⋅ K ⋅ τ V ⋅ 0.693 ⋅ N N⋅V
N
 1---
ss S⋅f⋅D  2
Cp min = ------------------ ⋅ --------------------- (EQ 10-18)
V 1 N
1 –  ---
 2
because errors involved with this approximation both in maximum and minimum
calculations (peak and trough) place the drug further within the Therapeutic
Range, i.e. the real peaks are lower than the calculated peaks and the real troughs
are higher than the calculated troughs, thus both errors are on the side of safety.
Dosing Interval The object of pharmacokinetics is to optimize therapy. By definition, that is to
maintain the plasma concentration of the drug within the therapeutic range for the
duration of the therapy presuming that is needed. Thus, the concentrations must
stay within the MTC and MEC or
ss
MTC- Cp max N
------------ = ------------------- = 2 max (EQ 10-19)
MEC ss
Cp min
by deviding equation 10-18 into equation 10-16 and simplifying. Given these lim-
its, the maximum dosing interval, τmax , is obtained by solving for Nmax:

Ln  ------------
MTC-
MEC
N max = -------------------------- (EQ 10-20)
Ln2
τ max
and since N max = ----------
- by definition,
t1 ⁄ 2
τ max = N max ⋅ t1 ⁄ 2 (EQ 10-21)
τ maxis not necessarily the dosing interval of choice, but it is the maximum dosing
interval attainable without sustained or controlled release delivery systems.
Accepable dosing intervals are those which result in a dose being given at the same
time of the day, every day. Imagine, if you will, the chaos on the nursing floor if
the dose for a given drug were every 15 hours. Compliance, none too high when
the patient is given a reasonable dosing interval, would go straight to the toilet if
we asked the patient to take a tablet every 5.3 hours. What would be optimal would
be to tie the takeing of the drug with an activity that occurs the same time every
day for once a day therapy, or at least dose the same time every day. Thus, for
multiple daily doses, the only regimens that work are those which when devide
into 24 hours give unit answers: QD = 24/1 = q24h; BID = 24/2 = q12h, TID = 24/
3 = q8h; QID = 24/4 = q6h; q4h; q3h; q2h. These result in decreasing orders of
patient compliance (unless the patient is really motivated to take the drug every 2
hours - forget it.) Thus the maximum acceptable dosing interval would be the larg-
est acceptable dosing interval below the τ max . So, for example if τ max is 15.7
hours, the maximum acceptable dosing interval would be 12 hours. we could also
dose every 8, 6 or 4 hours if necessary.

10.2 Diseases - Dosing the Compromised Patient

As previously discussed in the chapter on clearance, diseases result in changes in
clearance. These are routinely as a consequence of changes in organ function or
blood flow to the organ. Diseases which cause a change in clearance, do so by
changing either the elimination rate constant, K, or the volume of distribution, Vd,
or both. Thus the fractional change in total body clearance :
Cl tot ∗ K∗ ⋅ V∗
F Cl tot = -------------- = ------------------ (EQ 10-22)
Cl tot K⋅V
Where X* indicates new or changed variable. In general, if 0.80 < F Cl < 1.2 ,
tot
changes in dosage regimen are not necessary. In order to return a previously con-
trolled healthy pateint back to the therapeutic range, a general rule of thumb is sug-
gested as an initial starting point. The desease modifies K (as t1/2) and V. As
pharmacists, we can modify D and τ . These variables are paired in the above
equations (equation 10-16 and equation 10-18), D with V (in ⋅ f ⋅ D-
S----------------- ) and t1 ⁄ 2
V
τ
with τ (in N = --------- ). If the physiological change is a change in V, the pharmacist
t1 ⁄ 2
would recommend a change in D proportionally, and if the half life changes, the
pharmacist would recommend a change in the dosing interval proportionally.
Remenber, the object is to get the plasma concentrations back to where they were
prior to the illness. The only problem is that we are limited to these recommended
changes being incremental and not continuous. That is a change in dose is limited
to the available dosage forms and strengths and a change in dosing interval is
limeted to the accepatable dosing interval.
Protein Binding If the drug is highly protein bound, the object would be to get the free concentra-
tion back to what it was prior to illness. Consequently, equation 10-16, equation
10-17, and equation 10-18 would be rewritten thus:
ss ss fu ⋅ S ⋅ f ⋅ D 1
Cp = f u ⋅ Cp = -------------------------- ⋅ -------------------- (EQ 10-23)
1 –  1---
max free max V N
ss ss fu ⋅ S ⋅ f ⋅ D fu ⋅ S ⋅ f ⋅ D
Cp = fu ⋅ C p = -------------------------- = ------------------------------ (EQ 10-24)
avg free avg V⋅K⋅τ V ⋅ 0.693 ⋅ N

N
 1---
ss ss fu ⋅ S ⋅ f ⋅ D  2
Cp = fu ⋅ Cp = -------------------------- ⋅ -------------------- (EQ 10-25)
V N
1 –  1---
min free min
2
Some interesting and unexpected things result from these relationships. Since
plasma or blood concentrations are usually measured, if a drug is highly protein
bound and the desease results in upsetting that equilibrium, you might see toxicity
resulltling from normal or even subtherapeutic measured concentrations. More on
that in the chapter on protein binding.

10.3 Problems

Alprazolam (Problem 10 - 1)
Juhl, R. et al., "Alprazolam pharmacokinetics in alcoholic liver disease", Journal of Clinical Pharmacology, Vol.24, (1984), p. 113
- 119.
Alprazolam is an anti-anxiety agent which is metabolized to 4-hydroxy and α-hydroxy metabolites. In this
study, patients with cirrhosis of the liver and healthy patients were each given doses of 1.0 mg of Alpra-
zolam. The following data is for healthy patients.
PROBLEM TABLE 10 - 1. Alprazolam
Dose 1.0 mg BID
1.16 L/kg
1.22
529.3
AUC
Assume that your patient weighs 70 kg when answering the following:

1. Find k.
2. Find the MRT.
3. Find the .
4. Find the AUMC.
5. Find τ.
6. What is N?
7. What is the patient's maximum plasma concentration, , under this dosage regimen.
8. What is the patient's average plasma concentration, , under this dosage regimen.
9. What is the patient's minimum plasma concentration, , under this dosage regimen.

Cefixime (Problem 10 - 2)
Faulkner, R. et al., "Pharmacokinetics of cefixime after once-a-day and twice-a-day dosing to steady state", Journal of Clinical
Pharmacology, Vol.27, (1987), p. 807 - 812.
Cefixime is a broad-spectrum cephalosporin which is active against a variety of gram positive and gram negative bac-
teria. In this study, patients received a 200 mg oral dose of cefixime twice daily.
PROBLEM TABLE 10 - 2. Cefixime
Dose 200 mg BID
3.3 hours
286
32
AUC 14.12
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find τ.
7. What is N?

Cefpodoxime (Problem 10 - 3)
Borin, M. et. al., "Pharmacokinetics and tolerance studies of cepodoxime after single-and multiple-dose oral administration of cef-
podoxime proxetil", Journal of Clinical Pharmacology, Vol.31, (1991), p. 1137 - 1145.
Cefpodoxime proxetil is a third-generation, broad-spectrum cephalosporin which is given by the oral route. It is a pro-
drug which is converted in vivo to cefpodoxime which inhibits bacterial cell wall synthesis by binding to penicillin-
binding proteins.
PROBLEM TABLE 10 - 3. Cefpodoxime
Dose 100 mg BID
2.1 hours
271
79.1
AUC 6.9
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find τ.
7. What is N?

Cefprozil (Problem 10 - 4)
Lode, H. et. al., "Multiple-dose pharmacokinetics of cefprozil and its impact on intestinal flora of volunteers", Antimicrobial
Agents and Chemotherapy, Vol.36, (1992), p. 144 - 149.
Cefprozil is a broad-spectrum cephalosporin which is given by the oral route. In this study subjects received 500 mg
doses of cefprozil every twelve hours for eight days.
PROBLEM TABLE 10 - 4. Cefprozil
Dose 500 mg q. 12 hours
55.11minutes
310.25
277.50
AUC 27.80
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find τ.
7. What is N?

Clobazam (Problem 10 - 5)
Greenblatt, D. et. al., "Reduced single-dose clearance of clobazam in elderly men predicts increased multiple-dose accumulation",
Clinical Pharmacokinetics, Vol.8, (1983), p. 83 - 94.
Clobazam is an agent used in the treatment of anxiety. In this study, patients received 10 mg dose of clobazam daily.
PROBLEM TABLE 10 - 5. Clobazam
Dose 10 mg daily
180 hours
AUC
1. Find k.
2. Find MRT.
3. Find the ?
4. Find the AUMC.
5. Find τ.
6. What is N?
10. Your patients renal function drops to 50% of normal. What would be a new dosing regimen under these condi-
tions? (Assume that you want to keep < 110% of the normal and that you want to keep > 90% of the normal .)

Maloprim (Problem 10 - 6)
Edstein, M., Rieckmann, K., and Veenendaal, J., "Multiple-dose pharmacokinetics and in vitro antimalarial activity of dapsone
plus pyrimethamine (Maloprim) in man", British Journal of Clinical Pharmacokinetics, Vol.30, (1990), p.259 - 265.
Maloprim is an agent which contains both dapsone and pyrimethamine. In this study, healthy volunteers
were given 100 mg of dapsone plus 12.5 mg pyrimethamine weekly. The following data is for dapsone:
PROBLEM TABLE 10 - 6. Maloprim
Dose 100 mg weekly

22.6 hours
AUC 35.0
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find τ.
7. What is N?

Doxycycline (Problem 10 - 7)
Shmuklarsky, M. et. al., "Failure of doxycycline as a causal prophylactic agent against Plasmodium falciparum malaria in healthy
nonimmune volunteers", Annals of Internal Medicine, Vol.120, (1994), p. 294 - 298.
Doxycycline is an antibiotic which has been recommended for prevention of malaria in people traveling to areas
endemic to chloroquine-resistant P. falciparum malaria who are unable to take mefloquine. This study determined that
doxycycline is not effective for this use. Volunteers were given 100 mg doses of doxycycline daily for 10 days.
PROBLEM TABLE 10 - 7. Doxycycline
Dose 100 mg daily
21.9 hours
AUC 40.7
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find τ.
7. What is N?

DQ-2556 (Problem 10 - 8)
Nakashima, M. et. al., "Phase I study of DQ-2556, a new parenteral 3-quaternary ammonium cephalosporin antibiotic", Journal of
Clinical Pharmacology, Vol.33, (1993), p. 57 - 62.
DQ-2556 is a new broad-spectrum cephalosporin which is active against many bacteria including Pseudomonas aerug-
inosa. Subjects in this study were each given a 2000 mg infusion of DQ-2556 over 5 minutes every 12 hours for a total
of 9 doses.
PROBLEM TABLE 10 - 8. DQ-2556
Dose 2000 mg infusion over 5 minutes
17.6 L
8.5
7.1
AUC 241.0
1. Find Cl.
2. Find k.
3. Find the MRT.
4. Find the .
5. Find the AUMC.
6. Find τ.
7. What is N?

Erythropoetin (Problem 10 - 9)
Gladziwa, U., et al., "Pharmacokinetics of epoetin (recombinant human erythropoietin) after long term therapy in patients under-
going haemodialysis and haemofiltration", Clinical Pharmacokinetics, Vol.8, (1983), p. 83 - 94.
Erythropoetin is a regulatory hormone of red blood cells. In this study patients with end-stage renal disease were given
150 U/kg of epoetin three times a week.
PROBLEM TABLE 10 - 9. Glipizide
Dose 150 U/kg t.i.w.
7.7hours
Cl 5.4
Assuming that your patient weighs 65 kg, please determine the following:
1. Find k.
2. Find MRT.
3. Find the .
4. Find the AUC.
5. Find the AUMC.
6. Find τ.
7. What is N?

Flecainide (Problem 10 - 10)

Forland, S. et al., "Flecainide pharmacokinetics after multiple-dosing in patients with impaired renal function", Journal of Clinical
Flecainide acetate is a class 1C anti-arrhythmic agent which is used in the treatment of ventricular and supraventricular
arrhythmias. In this study, subjects were given doses of 100mg of flecainide orally twice daily.
PROBLEM TABLE 10 - 10. Flecainide
Dose 100 mg BID

7.4 L/kg
486
89
AUC 3.429
Assume that your patient weighs 70 kg when calculating the following:

1. Find Cl.
2. Find k.
3. Find the MRT.
4. Find the .
5. Find the AUMC.
6. Find τ.
7. What is N?

Glipizide (Problem 10 - 11)

Kradjan, W. et al., "Glipizide pharmacokinetics: effects of age, diabetes, and multiple dosing", Journal of Clinical Pharmacology,
Vol.29, (1989), p. 1121 - 1127.
Glipizide is a second-generation oral hypoglycemic agent used in the treatment of non-insulin-dependent (type II) dia-
betes. In this study, both diabetic and non-diabetic elderly men were each given doses of 2.5 mg of glipizide daily for
five days. The data for the non-diabetic group is given below.
PROBLEM TABLE 10 - 11.
Dose 2.5 mg daily

4.0 hours
0.47
AUC 2325.4
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find τ.
7. What is N?

Lomefloxacin (Problem 10 - 12)

Hunt, T. and Adams, M., "Pharmacokinetics and safety of lomefloxacin following multiple doses", Diagn Microbiol Infect Dis,
Vol.12, (1989), p. 181 - 187.
Lomefloxacin is a quinolone antibiotic which is useful against both Gram-positive and Gram-negative bacteria. It is
used in the treatment of urinary tract infections and lower respiratory tract infections. A dose of 400 mg of lomefloxa-
cin was given twice daily to healthy patients.
PROBLEM TABLE 10 - 12. Lomefloxacin
Dose 400 mg BID

7.32 hours
AUC 61.67
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find τ.
7. What is N?

Loratadine (Problem 10 - 13)

Radwanski, E. et al., "Loratadine: multiple-dose pharmacokinetics", Journal of Clinical Pharmacology, Vol.27, (1987), p. 530 -
533.
Loratadine is an antihistamine which is orally active. In this study, healthy, male volunteers were each given a 40-mg
loratadine capsule daily for ten days.
PROBLEM TABLE 10 - 13. Loratadine
Dose 40 mg daily
14.4 hours
AUC 96.0
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find τ.
7. What is N?

Methamphetamine (Problem 10 - 14)

Cook, C., et al., "Pharmacokinetics of oral methamphetamine and effects of repeated daily dosing in humans", Drug Metabolism
and Disposition, Vol.20, (1992), p. 856 - 861.
Methamphetamine is a CNS stimulant which is used in the treatment of attention deficit disorder and obesity. In this
study, subjects were given a 0.125 mg/kg dose of methamphetamine daily.
PROBLEM TABLE 10 - 14. Methamphetamine
Dose 0.125 mg/kg daily

8.46 hours
65.0
212
Assume that your patient weighs 70 kg when calculating the following:

1. Find k.
2. Find MRT.
3. Find the .
4. Find the AUC.
5. Find the AUMC.
6. Find τ.
7. What is N?

Mexiletine (Problem 10 - 15)

Gillis, A. and Kates, R., "Clinical pharmacokinetics of the newer antiarrhythmic agents", Clinical Pharmacokinetics, Vol.9, (1984),
p. 375 - 403.
Mexiletine is a class Ib antiarrhythmic agent. In this study, volunteers each received a 1600 mg dose orally each day.
PROBLEM TABLE 10 - 15. Mexiletine
Dose 1600 mg daily

380 L
681
1. Find k.
2. Find the MRT.
3. Find the .
4. Find the AUC.
5. Find the AUMC.
6. Find τ.
7. What is N?

Moxisylyte (Problem 10 - 16)

Costa, P. et al., "Multiple-dose pharmacokinetics of moxisylyte after oral administration to healthy volunteers", Journal of Phar-
maceutical Sciences, Vol.82, (1993), p. 968 - 971.
Moxisylyte is an α-adrenergic blocker which has been used in Europe for some times as a vasodilator in the
treatment of such disease states as age-associated mental impairment, acrocyanosis, Raynaud's syn-
drome, vascular cochlearvestibular disorders, glaucoma, and benign prostatic hyperplasia.
PROBLEM TABLE 10 - 16. Moxisylyte
Dose 240 mg BID

2.28 hours
AUC 11186
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find τ.
7. What is N?

Naproxen (Problem 10 - 17)

Ouweland, F. et. al., "Hypoalbuminaemia and naproxen pharmacokinetics in a patient with rheumatoid arthritis", Clinical Phar-
macokinetics, Vol.11, (1986), p. 511 - 515.
The pharmacokinetics parameters of naproxen were looked at in patients with rheumatoid arthritis in this study. A
patient received a dose of 500 mg of naproxen orally twice daily.
PROBLEM TABLE 10 - 17. Naproxen
Dose 500 mg BID

9.0 L
AUC 1134
1. Find Cl.
2. Find k.
3. Find the MRT.
4. Find the .
5. Find the AUMC.
6. Find τ.
7. What is N?

Nisoldipine (Problem 10 - 18)

Harten, J. et al., "Influence of renal function on the pharmacokinetics and cardiovascular effects of nisoldipine after single and
multiple dosing", Clinical Pharmacokinetics, Vol.16, (1989), p. 55 - 64.
Nisoldipine is a second-generation calcium-channel blocker which is under investigation for use as an anti-hyperten-
sive agent. Nisoldipine is mainly eliminated through liver metabolism with metabolites being excreted mainly in the
urine but also in the feces. The systemic clearance of nisoldipine depends greatly on liver blood flow.
PROBLEM TABLE 10 - 18. Nisoldipine
Dose 10 mg BID orally

7.9 hours
AUC 5.2
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the ?
5. Find the AUMC.
6. Find τ.
7. What is N?

Pefloxacin (Problem 10 - 19)

Bruno, D. et al., "Bayesian versus NONMEM estimation", , Vol. , (19 ), p. 657 - 668.
Pefloxacin is an antibiotic used to treat patients who are in the intensive care unit. For this study, patients were given a
400 mg dose of pefloxacin twice daily for eight days.
PROBLEM TABLE 10 - 19. Pefloxacin
Dose 400 mg BID

21.3 hours
Cl 3.77
1. Find k.
2. Find MRT.
3. Find the ?
4. Find the AUC.
5. Find the AUMC.
6. Find τ.
7. What is N?

Phenylpropanolamine (Problem 10 - 20)

Scherzinger, S., Rowse, R., and Kanfer, I., "Steady state pharmacokinetics and dose-proportionality of phenylpropanolamine in
healthy subjects", Journal of Clinical Pharmacology, Vol.30, (1990), p. 372 - 377.
Phenylpropanolamine is a sympathomimetic agent which is used both for its action as a nasal decongestant and its
action as an anorexiant. In this study healthy volunteers were given doses of 25 mg every four hours for a total of
seven doses. It was found that phenylpropanolamine is 77% renally excreted.
PROBLEM TABLE 10 - 20. Phenylpropanolamine
Dose 25 mg q. 4 hours
4.71 hours
4.08 L/kg
0.5
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the AUC.
5. Find the AUMC.
6. Find τ.
7. What is N?

Promethazine (Problem 10 - 21)

Taylor, G. and Houston, J., "Changes in the disposition of promethazine during multiple dosing in rabbits", Journal of Clinical
Promethazine is an agent used as an anti-histamine and a sedative. In this study rabbits weighing 2.7 to 3.3 kilograms
each received a 10 mg/kg dose of promethazine every 24 hours for 14 days.
PROBLEM TABLE 10 - 21. Promethazine
Dose 10 mg/kg
249 minutes
65.0
1. Find k.
2. Find MRT.
3. Find the ?
4. Find the AUC.
5. Find the AUMC.
6. Find τ.
7. What is N?

Rufloxacin (Problem 10 - 22)

Mattina, R. et al., "Pharmacokinetics of rufloxacin in healthy volunteers after repeated oral doses", Chemotherapy, Vol.37, (1991),
p. 389 - 397.
Rufloxacin is a broad-spectrum, fluoroquinolone antibiotic. In this study a patient was given a loading dose of 300 mg
of rufloxacin followed by 150 mg of rufloxacin daily for five days.
PROBLEM TABLE 10 - 22. Rufloxacin
Dose 150 mg daily

104 L
41
10
AUC 121.5
1. Find k.
2. Find the MRT.
3. Find the .
4. Find the AUMC.
5. Find τ.
6. What is N?

Velnacrine (HP 029) (Problem 10 - 23)

Puri, S. et al., "Multiple dose pharmacokinetics, safety, and tolerance of velnacrine (HP 029) in healthy elderly subjects: a poten-
tial therapeutic agent for Alzheimer's disease", Journal of Clinical Pharmacology, Vol.30, (1990), p. 948 - 955.
Velnacrine is an investigative agent which has central cholinergic action and may be beneficial in the treatment of
Alzheimer's disease. Healthy, elderly, men were given doses of 100 mg twice daily in this study. It was found that 30%
of the velnacrine dose was excreted unchanged.
PROBLEM TABLE 10 - 23. Velnacrine (HP 029)
Dose 100 mg BID
2.4 hours
AUC 809.5
1. Find k.
2. Find the MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find τ.
7. What is N?

10.4 Answers
Alprazolam
1. 0.0631 h-1
2. 15.85 hours
3. 10.98 hours
4. 8387.81
5. 12
6. 1.093
7. 23.19
8. 16.26
9. 10.876
Cefixime
1. 0.210 h-1
2. 4.76 hours
3. 14.164 L/h
4. 67.435 L
5. 62.224
6. 12
7. 3.64
8. 3.225
9. 1.177
10. 0.259
Cefpodoxime
1. 0.330 h-1
2. 3.03 hours
3. 14.49 L/h
4. 43.91 L
5. 20.905

6. 12
7. 5.714
8. 2.322
9. 0.575
10. 0.0442
Cefprozil
1. 0.0126 min-1
2. 76.51 minutes
3. 17.99 L/h
4. 23.83 L
5. 36.84
6. 12
7. 13.065
8. 20.98
9. 2.317
10. 2.45
Maloprim
1. 0.0307 h-1
2. 32.6 hours
3. 2.857 L/h
4. 93.16 L
5. 1141.17
6. 168
7. 7.435
8. 1.08
9. 0.208
10. 6.25
Doxycycline
1. 0.0317 h-1

2. 31.595 hours
3. 2.457 L/h
4. 77.629 L
5. 1285.92
6. 24
7. 1.096
8. 2.42
9. 1.696
10. 1.133
DQ-2556
1. 8.299 L/h
2. 0.4715 h-1
3. 2.12 hours
4. 1.47 hours
5. 511.11
6. 12
7. 8.163
8. 114
9. 20.083
10. 0.398
Erythropoetin
1. 0.09 h-1
2. 11.11 hours
3. 3599.24 mL
4. 30092.6
5. 334291.14
6. 72
7. 9.35
8. 2713.24

9. 417.98
10. 4.156
Glipizide
1. 0.173 h-1
2. 5.77 hours
3. 1.075 L/h
4. 6.204 L
5. 13419.37
6. 24
7. 6
8. 0.4094
9. 96.893
10. 6.396
Flecainide
1. 29.16 L/h
2. 0.0563 h-1
3. 17.76 hours
4. 12.31 hours
5. 60.91
6. 12
7. 0.975
8. 0.393
9. 0.286
10. 0.200
Lomefloxacin
1. 0.0947 h-1
2. 10.56 hours
3. 6.486 L/h
4. 68.497 L

5. 651.27
6. 12
7. 1.639
8. 8.6
9. 5.139
10. 2.76
Loratadine
1. 0.0481 h-1
2. 20.77 hours
3. 416.67 L/h
4. 8656.17 L
5. 1994.38
6. 24
7. 1.67
8. 6.746
9. 4
10. 2.125
Methamphetamine
1. 0.082 h-1
2. 12.21 hours
3. 46.7 L
4. 2.244
5. 27.383
6. 24
7. 2.837
8. 213.74
9. 93.48
10. 29
Moxisylyte

1. 0.304 h-1
2. 3.29 hours
3. 0.0215 L/h
4. 70.574 mL
5. 36794.61
6. 12
7. 5.263
8. 3.492
9. 0.9322
10. 0.0909
Naproxen
1. 0.441 L/h
2. 0.049 h-1
3. 20.412 hours
4. 14.149 hours
5. 23147.21
6. 12
7. 0.848
8. 124.98
9. 94.5
10. 69.43
Mexiletine
1. 0.1075 h-1
2. 9.3 hours
3. 6.45 hours
4. 39.16
5. 364.17
6. 24
7. 3.723

8. 4.256
9. 1.632
10. 0.345
Nisoldipine
1. 0.0877 h-1
2. 11.397 hours
3. 1923.08 L/h
4. 21.92 mL
5. 59.27
6. 12
7. 1.52
8. 700.7
9. 433.3
10. 244.5
Pefloxacin
1. 0.0325 h-1
2. 30.73 hours
3. 115.85 L
4. 106.1
5. 3260.4
6. 12
7. 0.563
8. 10.68
9. 8.84
10. 7.23
Phenylpropanolamine
1. 0.147 h-1
2. 6.795 hours
3. 36.03 L/h

4. 0.694
5. 4.715
6. 4
7. 0.849
8. 229.5
9. 173.5
10. 127.4
Promethazine
1. 0.167 h-1
2. 5.987 hours
3. 70.05 L
4. 2.56
5. 15.35
6. 24
7. 5.78
8. 436.19
9. 106.84
10. 7.92
Rufloxacin
0.0237 h-1
42.28 hours
29.30 hours
5136.6
24
0.819
3.33
2.54
1.89
Velnacrine

1. 0.289 h-1
2. 3.462 hours
3. 123.53 L/h
4. 427.73 L
5. 2802.87
6. 12
7. 5
8. 241.33
9. 67.46
10. 7.54

`PHARMACOKINETICS: MAMMILLARY MODELS
For many drugs, the equilibrium between drug concentrations in different tissues is not achieved
rapidly. Thus, one of the assumptions of the one-compartment open model sometimes becomes
invalid. A more complex mammillary open model is often necessary to describe mathematically
the plasma concentration data (for example) seen after the administration of some drugs. The
simplest mammillary open model is a two-compartment open model where the drug is both
introduced into and exits from the central compartment ; for example:
X0
k12
X1 X2
k21
k10
• Compartment One (X1, the central compartment) can be sampled through the blood
(or plasma, or serum). It may consist of organs or tissues which, being highly
perfused with blood, are in rapid equilibrium distribution with the blood.
• Compartment Two (X2, the peripheral compartment) cannot normally be sampled. It

may consist of organs or tissues which, being poorly perfused with blood, are in slow
equilibrium distribution with the blood.
• The Body is the sum of both compartments.
1. Intravenous Bolus Administration: Plasma Concentration Data

Recall that for a one-compartment open model, the plasma concentration follows the
equation:
Cp = Cp0 e( − kT ) (11.1.1)
Plasma Concentration vs. Time
1000
Plasma Concentration
100
10
0 5 10 15 20 25 30
Time
i.e., the
concentration of drug in the plasma declines mono-exponentially with time (one
straight line on semi-log paper.)
2. Bi-exponential Properties of Two-Compartment Open Model
Following an intravenous bolus injection, the plasma concentration against time profile
has two phases:
a. Initial phase - (α - phase)
b. Terminal phase - (β - phase)
Plasma Concentration vs. Time
1000
Alpha Phase
Plasma Concentration
Beta Phase
100
10
0 5 10 15 20 25 30
Time
On semilogarithmic paper (logarithm on the Y axis), the terminal phase is linear,

indicating that initial distribution has been completed and that equilibrium has
been attained. The terminal half life (T½β ) can be measured from the terminal
phase.
For a two-compartment open model, The plasma concentration follows the

equation:
Cp = A1e( ) + B1e( )
−α T − βT
(11.1.2)
i.e., the concentration of drug in the plasma declines bi-exponentially with

time.
2.1 Symbols
i. A1 and B1 are intercept constants (m/L3)

ii. α and β are hybrid rate constants (T-1)
iii. V1 is the apparent volume of unchanged drug distribution in compartment
1 (L3)
iv. k10, k12, and k21 are the “micro” rate constants (T-1)
2.2 Relationships:
1
2 (
α = ( k10 + k12 + k21 ) + ( k10 + k12 + k21 )
2
)
− 4 ( k10 k21 ) (11.1.3)
1
2 (
β = ( k10 + k12 + k21 ) − ( k10 + k12 + k ) − 4(k k ) )
21
2
10 21 (11.1.4)
D (α − k21 )
A1 = (11.1.5)
V1 (α − β )
D ( k21 − β )
B1 = (11.1.6)
V1 (α − β )
Cp0 = A1 + B1 (11.1.7)
α + β = k12 + k10 + k21 (11.1.8)
αβ = k10 k21 (11.1.9)
2.3 Obtaining Pharmacokinetic Parameters by “Feathering”

By convention, α > β
a. Plot Cp against t on semilogarithmic paper
b. Find t½ from the linear terminal phase: see “Intravenous
Administration,” section A1.4a
c. Calculate the terminal hybrid rate constant (β); in reality it
contains both distributive (k12 and k21) and elimination (k10)
factors.
ln(2)
β= (11.1.10)
(t 1 2 ) β
d. Draw a straight line through the linear terminal elimination phase

HJJ is equal to B1.
and extrapolate this line to t = 0. The intercept
e. Read extrapolated plasma concentrations C p from the plot at times
equal to those given for values of Cp which are prior to the
terminal phase.
f. At each of these times, calculate:
HJJ
C p diff = C p − C p (11.1.11)
g. Plot C p diff against t on semilogarithmic paper. The plot is a
“feathered” line and should decline linearly.
h. Find the half-life of the plot. It will refer to the initial phase.
Calculate,
ln(2)
α= (11.1.12)
(t 1 2 )α
i. Measure the intercept of the “feathered” line; it will be equal to A1

(note that A1 ≠ B1, even theoretically).
j. Calculate (Cp)o from Eq. (11.1.7)
k. Calculate V1 by
X0 Dose
V1 = = (11.1.13)
Cp0 A1 + B1
Theory (Why does feathering work?)
When t is large, e-αt < e-βt. Hence, Eq (11.1.2) becomes

Cp = B1e( − β T ) (11.1.14)
i.e., when t is large, the concentration of the drug in the plasma
declines exponentially with time.
The extrapolated plasma
HJJ
concentrations are
Cp = B1e( )
− βT
(11.1.15)
Substituting from Eqs. (11.1.2)and (11.1.15) into Eq.(11.1.11),
C pdiff = A1e( −αT ) (11.1.16)
i.e., the difference between observed and extrapolated drug
concentrations in the plasma declines exponentially with
time.
Note: The micro rate constants in terms of the graphical variables are:
α B1 + β A1
k21 = (11.1.17)
A1 + B1
αβ αβ ( A1 + B1 )
k10 = = (11.1.18)
k21 α B1 + β A1
A1 B1 (α − β )
2
k12 = α + β − k10 − k21 = (11.1.19)

(α B1 + β A1 )( A1 + B1 )
2.4 Clearance and Volume Concepts
If model-independent equations can be used to define these terms, this is
preferred.
a. Systemic Clearance (C1) may be calculated by,
Dose
Cl = (11.1.20)
AUC0∞
b. The volume terms are more complex than in a one-compartment
open model. There are two terms of interest:
The apparent volume of distribution in compartment one (V1) -
This is calculated using Eq.(11.1.15)
The apparent volume of distribution at pseudo-distribution
equilibrium (Vβ)
This volume may be defined only in relation to the terminal
phase (β-phase), when initial distribution has been
completed. It may be calculated by,
Dose
Vβ = (11.1.21)
β AUC0∞
As Vβ requires calculation of the total area under the
plasma concentration against time curve, it is also known
as Varea.
c. Comparing Eqs. (11.1.20)and (11.1.21),
Cl = βVβ (11.1.22)
It may also be shown that,
Cl = k10V1 (11.1.23)
This follows as systemic clearance is always given by the
elimination rate constant out of the body multiplied by the
apparent volume of distribution in the compartment from which
drug leaves the body. Comparing Eqs. (11.1.22) and (11.1.23),
k
Vβ = 10 V1 (11.1.24)
β
Note that k10 (the elimination rate constant) is not the same as β
(the terminal hybrid rate constant).
2.5 Bioavailability
Find (AUC)0 using trapezoidal rule and, if necessary, the calculation for
the terminal area.
tlast
Cp
AUC0∞ = ∑ AUC + last (11.1.25)
0 β
This is a model-independent equation.
2.6 Dosage Regimens

The maintenance dose (DoseM) is given by the same model-independent
equation as before,
DoseM = C p Clτ ( ) ss
(11.1.26)
( )
Where C p
ss
has its same previous definition.
The loading dose (DoseL) achieves a steady-state condition quite rapidly,
but only after initial distribution has been completed. It is given by the
previous equation,
DoseM
DoseL = (11.1.27)
()
N
1 − 12
( )
As may be expected, equations relating (Cmax)ss and (Cmin)ss to Cp
ss
are
as before.
All dosage regimen equations strictly apply only when,

β  k12 
1 +  ≈1 (11.1.28)
k10  k21 
Eq. (11.1.28) has the value of
0.947 for digoxin
0.990 for warfarin
0.846 for cephalexin
This is why, despite the fact that an open two-compartment model is the
better description of the pharmacokinetics of these drugs, a simple one-
compartment model may often be assumed for dosage regimen purposes.
3. Intravenous Bolus Administration: Compartment Two
It is not normally possible to measure drug concentrations in compartment two.
However, the mass of drug can be predicted based on the drug concentrations
observed in compartment one.
α −β
e (
k Dose ( − β T ) ( −α T )
X 2 = 12 −e ) (11.1.29)
Note that the equation form bears a similarity to that seen for plasma
concentrations after oral administration into a one-compartment open
model.
When t is large, e-αt < e-βt. Hence, Eq. (11.1.29) becomes,

k Dose ( − β T )
X 2 = 12
α −β
e ( ) (11.1.30)
This is compared to the mass modification of Eq.(11.1.14),

X 1 = V1 B1e( )
− βT
(11.1.31)
Thus, when t is large, the masses of drug in each compartment decline
exponentially, and in parallel, with time. This indicates that equilibrium attained.
If the value of X2 reflects drug concentrations at the active site, the time of
maximum concentration (and maximum pharmacological effect) is:
 
Ln  αβ 
tmax =  
(11.1.32)
α −β
4. Other Dosage Forms
The equations become complex and it is therefore difficult to obtain useful

parameter values without the aid of a computer. Fortunately, because the
complexity of the equations is greater than the experimental accuracy of the
assays warrants, drugs that strictly require a mammillary model can be described
adequately by an open one-compartment model for the purposes of calculating
dosage regimens.
4.1 Intravenous Infusion
The plasma concentrations at first rise faster than an open one-

compartment model profile would suggest. Later, the rise is slower. The
decline, following the cessation of infusion, is bi-exponential.
Cp =
Q

(
 ( k21 − β ) 1 − e − β t
−
) (
( k21 − α ) 1 − e−α t )  (11.1.33)
V1 (α − β )  β α 

Where α is as before in equation (11.1.3)

β is as before in equation (11.1.4)
Q is the infusion rate
V1 is as before in equation (11.1.2)
Cpss would be given by setting time equal to infinity and reducing
equation (11.1.33) to
Q Q
Cpss = = (11.1.34)
V1k10 Clearance
If theer infusion was terminated at time T, the concentration at time T

would be given by substituting T for t in equation (11.1.33) and the
concentration after time T would be given by
Cp =
Q

( −
) (
 ( k21 − β ) e β T − 1 e − β t ( k21 − α ) eαT − 1 e−α t 

) (11.1.35)
V1 (α − β )  β α 

4.2 Oral Administration
100
Concentration
10
0 2 4 6 8 10 12
Time
At a time just after tmax the plasma concentration may exhibit a “nose,” when
compared to the profile of an open one-compartment model if the absorption
rate is significantly larger than α and β . The terminal rate constant will be
reflected by the smallest rate constant usually β but sometimes it could be Γ,
the absorption rate constant.
Cp = A1e −α t + B1e − β t + C1e −γ t (11.1.36)

Where α is as before in equation (11.1.3)
β is as before in equation (11.1.4)
γ = ka, the absorption rate constant
D ( k21 − α ) γ
A1 = (11.1.37)
V1 ( γ − α )( β − α )
D ( k21 − β ) γ
B1 = (11.1.38)
V1 ( γ − β )(α − β )
D ( k21 − γ ) γ
C1 = (11.1.39)
V1 (α − γ )( β − γ )
Cp0 = A1 + B1 + C1 = 0 (11.1.40)
SELECTED REFERENCES
Riegelman, S., Loo, J.C.K., and Rowland, M., Shortcomings in pharmacokinetic analysis by
conceiving the body to exhibit properties of a single compartment, J. Pharm. Sci., 57, 117-123
(1968).
Riegelman, S., Loo, J.C.K., and Rowland, M., Concept of a volume of distribution and possible
errors in evaluation of this parameter, J. Pharm.Sci., 57, 128-133 (1968).
Benet, L.Z. and Ronfeld, R.A., Volume terms in pharmacokinetics, J. Pharm. Sci., 58, 639-641
(1969).
Gibaldi, M., Nagashima, R., and Levy, G., Relationship between drug concentrations in plasma
or serum and amount of drug in the body, J. Pharm.Sci., 58, 193-197 (1969).
Metzler, C.M., Usefulness of the two-compartment open model in pharmacokinetics, J. Amer.

Stat. Assn., 66, 49-54 (1971).
Gibaldi, M. and Perrier, D., Drug elimination and apparent volume of distribution in
multicompartment systems, J. Pharm. Sci., 61, 952-954 (1972).
Gillette, J.R., The importance of tissue distribution in pharmacokinetics, J. Pharmacokin.

Biopharm., 1, 497-520 (1973).
Drug Disposition: Volume Terms
As apparent volumes of distribution are proportionality constants, and not physilological spaces,
more than one term is of value.
1. Apparent Volume of sampled compartment (V1)
This relates the concentration of drug on the sampled compartment with the mass of drug
in that compartment.
It may be calculated after an intervenous dose by:

Dose Dose
V1 = = (11.2.1)
K ( AUC )
∞
C p0
0
It may be calculated after an intervenous infusion by

X Q
V1 = 1ss = (11.2.2)
(
C pss K C p
ss
)
2. Apparent Volume at Pseudo-Distribution Equilibrium (Vβ)
This volume term (sometimes known as the apparent volume of distribution of the drug
in the body) requires the assumption that the drug is evenly distributed throughout the
body which is clearly not true in most cases. Thus Vβ is only defined in relationship to
the terminal phase (β phase) after equilibrium has been attained. It is calculated by:
Dose
Vβ = (11.2.3)
β ( AUC )0
∞
3. Relationships between apparent volumes:

Clearance (Cl) is calculated by the first order rate constant for the removal of the drug
from the body multiplied by the volume of distribution of the drug in the compartment
from which the drug leaves the body:
Clr = krV1 (11.2.4)
Clm = kmV1 (11.2.5)
Cls = KV1 (11.2.6)
However, systemic clearance is calculated by:

Dose
Cls = (11.2.7)
( AUC )0
∞
Comparing Eqs (11.2.3) and (11.2.7) we find:

Cls = βVβ (11.2.8)
And comparing Eqs (11.2.6) and (11.2.8) we find
K
Vβ = V1 (11.2.9)
β
As K > β, then Vβ >> V1. Note that if the pharmacokinetics cam be described by the one
compartment model, then β = K and Vβ = V1.
Selected References
Riegelman, S., Loo, J.C.K. and Rowland, M., Concept of volume of distributions and possible
errors in evaluation of this parameter, J. Pharm. Sci., 57, 128-133 (1968)
Benet, L.Z. and Ronfeld, R.A., Volume terms in pharmacokinetics, J. Pharm. Sci. 58, 639-641
(1969)
Gibaldi, M., Nagashima, R., and Levy, G., Relationship between drug concentrations in plasma
or serum and the amount of drug in the body. J. Pharm. Sci., 58, 193-197 (1969)
Perrier, D. and Gibaldi, M., Relationship between plasma or serum drug concentrations and the
amount of drug in the body at steady state upon multiple dosing, J. Pharmacokin. Biopharm., 1,
17-22 (1973)
Oie, S. and Tozer, T.N., Effect of altered plasma protein binding on apparent volumes of
distribution, J. Pharm. Sci., 68, 1203-1205 (1979)
Linear Mamillary Models and the LaPlace Transform
Drug is usually sampled from the central compartment, designated as compartment one.
1. Laplace transform for Compartment One
As ,1 = (in)(d s ,1 ) (11.3.1)
Where:
A s,1 is the Laplace transform for the mass of the drug in
compartment one
s is the Laplace Operator
in is the input function
ds,1 is the disposition function for compartment one.
2. Input functions
(Note: Input need not be into compartment one)
a. IV Bolus
(in) = D (11.3.2)
Where: D is the dose.
b. IV Infusion
Q(1 − e − sb )
(in) = (11.3.3)
s
Where: Q is the zero oder infusion rate,
b =t when t<Term
b=T when t>=Term
and Term is the termination time of the infusion
c. First order absorption

ka FD
( in ) = (11.3.4)
( s + ka )
Where: ka is the first order absorption rate constant
F is the fraction of the dose that ultimately reaches
systemic absorption.
d. Dissolution and absorption (Type 1)

kr ka FD
( in ) = (11.3.5)
( s + kr )( s + ka )
Where: kr is the first order dissolution rate constant
e. Dissolution and absorption (Type 2)

k k (1 − e − sb )
( in ) = 0 a (11.3.6)
s ( s + ka )
Where: k0 is the zero order dissolution rate constant, ceasing at
time T
f. Others
More complex functions can be derived simply by the serial addition of the above
functions, e.g.:
Q(1 − e − sb )
(in) = D + (11.3.7)
s
Denote the simultaneous commencement of an IV bolus and IV infusion.
3. Disposition Function for Compartment One

A driving force compartment has one or more exit rate constants; for example, in
compartment i, the sum of the first order rate constants is Σi. Then:
i=n
kq1 ∏ ( s + Σi )
i=2
(d ) =
s ,1
i≠q
 
(11.3.8)
i=n j =n m=n
 
∏ ( s + Σ i ) − ∑ 
j =2 
k1 j j1 ∏ ( s + Σ m ) 
k
i =1 m=2 
 m≠ j 
Where: q is the compartment into which the input
occurs
n is the number of driving force compartments
i,j are counters (maximum of n)
kq1 is the first order rate constant for transfer of
drug from the input compartment into
compartment one
k1j, kj1 are the first order rate constants for drug
transfer from compartment one to
compartment j and visa versa.
a. Using the disposition function:

i. If q = 1, then kq1 = 1
ii. Πi and Πm are continued products. The value equals one when the
counter I or m takes on a forbidden number. For example i=1 is
forbidden in the numerator and m=1 and m=j are forbidden in the
denominator.
b. Examples
i. One compartment open model (n=1,q=1)
d s ,1 = 1 (11.3.9)
ii. Two compartment open models (n=2,q=1)
d s ,1 =
( s + Σ2 ) (11.3.10)
( s + Σ1 )( s + Σ 2 ) − k12 k21
iii. Three compartment open models (n=3,q=2)
k21 ( s + Σ3 )
d s ,1 = (11.3.11)
( s + Σ1 )( s + Σ 2 )( s + Σ3 ) − k12 k21 ( s + Σ3 ) − k13k31 ( s + Σ 2 )
c. Simplifying the denominator
The number of exponential terms in the final integrated equation will be equal to
the number of driving force compartments (n.) This is also equal to the maximum
power to which the LaPlace operator (s) would appear if the denominator were
i =n
multiplied out. Hence, the denominator is simplified to become ∏ ( s + k ) where
i =1
i
ki is a composite rate constant. Thus for the:

One compartment model:
1
d s ,1 = (11.3.12)
( s + k1 )
Two compartment models
d s ,1 =
( s + Σ2 ) (11.3.13)
( s + k1 )( s + k2 )
Three compartment models
k21 ( s + Σ3 )
d s ,1 = (11.3.14)
( s + k1 )( s + k2 )( s + k3 )
The exact meaning of ki for any model depends on the equalities evident in the
denominators.
For example for the two compartment model
( s + k1 )( s + k2 ) = ( s + Σ1 )( s + Σ 2 ) − k12 k21 (11.3.15)
And the right side of equation (11.3.15) can be multiplied out to the resultant
quadratic equation as 2 + bs + c which is subsequently factored using the equation
−b ± b 2 − 4ac
to solve for the roots of a quadratic equation ki =
2a
4. Method of partial fractions
This method is used to solve the LaPlace transform provided that there are NO repeating
factors in the denominator. E.g. NO s2 or (s+ki)2.
a. Prepare the LaPlace transform, e.g. IV Bolus into the two compartment model:
D ( s + Σ2 )
as ,1 = (11.3.16)
( s + k1 )( s + k2 )
b. Obtain the roots
For (s+k1) the root is –k1
For (s+k2) the root is –k2
If the factor is s the root is 0.
c. The “Hidden Hand” Method

i. Deal with each factor in turn.
ii. Cover each factor and remember its root.
iii. Whenever the LaPlace operator occurs in the uncovered transform,
substitute the root for s
iv. Multiply the result by est, again substituting the root for s.
v. After doing 2 through 4 for each factor, simplify.
For the two compartment model the result would be:
D ( − k1 + Σ 2 ) − k1t D ( − k2 + Σ 2 ) − k 2t
X1 = e + e (11.3.17)
( −k1 + k2 ) ( −k2 + k1 )
which can take the form of:
C1 = A1e −α t + B1e − β t (11.3.18)
with the exact meanings of the variables dependent on the form of the
model.
5. LaPlace Transfom for peripheral compartments

This is analogous to that of employed when using the LaPlace transform table.
a. Draw the model.
b. Write the differential equation using all the arrows which touch the box
(compartment) in question.
c. Take the transform of each side of the equation using the table where necessary.
d. Use algebra to get the single time dependent variable on the left side and
everything else on the right side.
e. Substitute for any know transformed dependent variables on the right side of the
equation.
f. Solve using the “Hidden Hand” method above and simplify.
6. Method if the denominator contains the factor s2.

The “Hidden Hand” method is not applicable for the factor s2 as it has no simple root.
The S2 factor may show up in terminal compartments, such as urine, following an IV
infusion.
a. Example (n=2,q=1, exit from compartment one)
(
as ,u = k10Q 2
)
1 − e − sb ( s + Σ 2 )
(11.3.19)
s ( s + k1 )( s + k2 )
where: k10 is the first order excretion rate constant from
compartment one.
and this results in:
Σb
X u = k10Q 2 + .... (11.3.20)
k1k2
where Xu is the cumulative mass of drug excreted into the urine
and the other factors are handled by the “Hidden Hand” method as
above.
b. Example (n=3,q=1, exit from compartment one)
as ,u = k10Q 2
( )
1 − e − sb ( s + Σ 2 )( s + Σ3 )
(11.3.21)
s ( s + k1 )( s + k2 )( s + k3 )
and this results in:
ΣΣb
Xu = k10Q 2 3 + ... (11.3.22)
k1k2 k3
References
L.Z.Benet, General treatment of linear mamilary models with elimination from any compartment
as used in pharmacokinetics, J. Pharm. Sci., 61 536-541 (1972)
D.P. Vaughan, D.J.H. Mallard, A. Trainor, and M. Mitchard, General pharmacokinetic equations
for linear mammillary models with drug absorption into peripheral compartments, Europ. J. Clin.
Pharmacol., 8, 141-148 (1975)
D.P. Vaughn and Trainor, Derivation of general equations for linear mammillary models when
drug is administered by different routes, J/ Pharmacokin. Biopharm., 3, 203-218 (1975)
Aspirin
Fu, C., Melethil, S., and Mason, W., "The pharmacokinetics of aspirin in rats and the effect of
buffer", Journal of Pharmacokinetics and Biopharmaceutics, Vol. 19, (1991), p. 157 - 173.
Aspirin is an analgesic/ antipyretic commonly used to relieve minor pain and is

used in such conditions as rheumatic fever, rheumatoid arthritis, and osteoarthritis. The
major metabolite of aspirin is salicylic acid. The following set of data was collected
using rats which weighed 250 - 300 g. Graph the data and find A1, α, B1, β. Check
your answers with the answers given below and answer the remaining questions using
the correct answers.
Time(hr) Time(min) Cp(mg/L)
0.000 0.000 15.820
0.001 0.065 15.152
0.005 0.324 12.853
0.011 0.648 10.650
0.022 1.296 7.732
0.032 1.943 5.981
0.058 3.466 3.830
0.116 6.931 1.815
0.173 10.397 0.905
0.289 17.329 0.226
0.433 25.993 0.040
0.578 34.657 0.007
weight of rat 275 g
Dose 5 mg/kg IV
µg
A1 8.58
mL
α 1.07 min −1
µg
B1 7.24
mL
β 0.2 min −1
µg
AUC 38.8 ⋅ min
mL
AUMC µg
116.0 ⋅ min 2
mL
1. What is AUCα ?
2. What is AUCβ ?
3. What is your patient's clearance?
4. What is your patients MRT?
5. What is your patient's Vβ ?
6. What is your patient's V1?
7. What is your patient's Vd ss ?
8. What is t 1 2 (α ) ?
9. What is t 1 2 ( β ) ?
10. What is k21 ?
11. What is k10 ?
12. What is k12 ?
13. What is Cpo ?
14. What is the t max in the peripheral compartment?
15. What percent of the dose is in the peripheral compartment at equilibrium?
16. Can this drug be treated as a one-compartment model for dosing purposes?
17. If this drug can be treated as a one-compartment model, what is K ?
18. What would be the Cpmax and Cpmin if the patient were dosed as above by IV
bolus every four hours?
Buprenorphine
Ohtani, M., et al., "Pharmacokinetic analysis of enterohepatic circulation of buprenorphine and
its active metabolite, norbuprenorphine, in rats", Drug Metabolism and Disposition, Vol. 22,
(1994), p. 2 - 7.
Buprenorphine is a morphine derivative which has twice the duration of action

and 30 times the potency of morphine. Buprenorphine is partially metabolized to
norbuprenorphine which is also active in the body. In this study, buprenorphine was
given to rats weighing 280 - 300 g. Graph the data and find A1, α, B1, β. Check your
answers with the answers given below and answer the remaining questions using the
correct answers.

0.000 0.000 0.051
0.018 1.069 0.048
0.089 5.346 0.039
0.178 10.691 0.030
0.356 21.382 0.019
0.535 32.074 0.014
2.558 153.464 0.005
5.115 306.929 0.003
7.673 460.393 0.001
Weight of rat 290 g
Dose 0.06 mg/kg IV
ng
A1 41
mL
α 3.89 hr −1
ng
B1 10
mL
β 0.271 hr −1
ng
AUC 48.3 ⋅h
mL
AUMC ng 2
135.24 ⋅h
mL
1. What is AUCα ?
2. What is AUCβ ?
4. What is your patients MRT?
8. What is t 1 2 (α ) ?
9. What is t 1 2 ( β ) ?
10. What is k21 ?
11. What is k10 ?
12. What is k12 ?
13. What is Cpo ?
Caffeine
Shi, J., et al., "Pharmacokinetic-pharmacodynamic modeling of caffeine: Tolerance to pressor
effects", Clinical Pharmacology and Therapeutics, Vol. 53, (1993), p. 6 - 14.
This study looks at the cardiovascular effects of caffeine. Caffeine is known to

increase blood pressure upon its withdrawl. This study looks at how tolerance to
caffeine and its pressor effects develops and disappears with time. Graph the data and
find A1, α, B1, β. Check your answers with the answers given below and answer the
remaining questions using the correct answers.

0.000 0.000 19.650
0.014 0.849 18.914
0.071 4.244 16.413
0.141 8.488 14.084
0.283 16.975 11.164
0.424 25.463 9.573
3.014 180.821 4.550
6.027 361.642 2.275
9.041 542.463 1.138
15.068 904.105 0.284
22.603 1356.158 0.050
30.137 1808.210 0.009
Patient weight 80 kg
Dose 4 mg/kg oral
µg
A1 10.55
mL
α 4.9 hr −1
µg
B1 9.1
mL
β 0.23 hr −1
f 98.4 %
1. What is AUCα ?
2. What is AUCβ ?
3. What is AUCtotal ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Cefazolin
Nightingale, C., et al., "Changes in pharmacokinetics of cefazolin due to
stress", Journal of Pharmaceutical Sciences, Vol. 64, (1975), p. 712 - 714.
Cefazolin is a cephalosporin antibiotic used in the treatment of many types of

infections. This study looks at the effect of stress on the pharmacokinetics of cefazolin.
The following data was approximated from the graph given in this article. Graph the
data and find A1, α, B1, β. Check your answers with the answers given below and
answer the remaining questions using the correct answers.

0.000 0.000 329.440
0.014 0.861 314.606
0.072 4.303 264.012
0.143 8.607 216.497
0.287 17.214 155.940
0.430 25.821 121.899
1.210 72.581 62.078
2.419 145.162 30.742
3.629 217.743 15.370
6.048 362.904 3.843
9.073 544.356 0.679
12.097 725.809 0.120
Patient weight 56.3 kg
Dose 1 g IV
µg
A1 206.48
mL
α 4.832 hr −1
µg
B1 122.96
mL
β 0.573 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Ceftazidime
Ackerman, B., et al., "Effect of decreased renal function on the pharmacokinetics of
ceftazidime", Antimicrobial Agents and Chemotherapy, Vol. 25, (1984), p. 785 - 786.
Ceftazidime is a cephalosporin antibiotic. This study explores the effect of

compromised renal function on the pharmacokinetics of ceftazidime. The following data
was approximated from the graph given in this article. Graph the data and find A1, α,
B1, β. Check your answers with the answers given below and answer the remaining
questions using the correct answers.
Time(hr)Time(min) Cp(mg/L)
0.000 0.000 246.200
0.008 0.506 233.370
0.042 2.530 189.946
0.084 5.059 149.844
0.169 10.119 100.584
0.253 15.178 74.915
1.415 84.875 29.102
2.829 169.750 14.550
4.244 254.625 7.275
7.073 424.376 1.819
10.609 636.564 0.322
14.146 848.752 0.057
Dose 1 g IV bolus
mg
A1 188
L
α 8.22 hr −1
mg
B1 58.2
L
β 0.49 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
2-Chloro-2-deoxyadenosine
Liliemark, J. and Juliusson, G., "On the pharmacokinetics of 2-Chloro-2-deoxy-
adenosine in humans", Cancer Research, Vol. 51, (1991), p. 5570 - 5572.
Two-Chloro-2-deoxyadenosine is an antitumor agent used in the treatment of

hairy cell leukemia and other lymphoproliferative diseases. Infusions of 0.14 mg/kg
over 12 hours were administered to 12 patients with various lymphoproliferative
diseases for 5 consecutive days. Answer the remaining questions given this analysi of
the data.
Dose 0.14 mg/kg over 12 hours
A1 177.0 nM
α 1.04 hr −1
B1 21.0 nM
β 0.10 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Clentiazem
Shah, A., et al., "Pharmacokinetics of clentiazem after intravenous and oral administration in
healthy subjects", Journal of Clinical Pharmacology, Vol. 33, (1993), p. 354 - 359.
Clentiazem is an derivative of diltiazem which is under investigation for its use in

the treatment of angina pectoris and hypertension. Clentiazem blocks calcium channels
resulting in a decrease in peripheral vascular resistance which subsequently leads to a
decrease in blood pressure. Graph the data and find A1, α, B1, β. Check your answers
with the answers given below and answer the remaining questions using the correct
answers.
0.000 0.000 0.054
0.026 1.540 0.051
0.128 7.702 0.043
0.257 15.403 0.035
0.513 30.807 0.025
0.770 46.210 0.020
8.887 533.190 0.008
17.773 1066.380 0.004
26.660 1599.570 0.002
44.433 2665.951 0.001
Dose 20 mg IV bolus
ng
A1 37.52
mL
α 2.7 hr −1
ng
B1 16.17
mL
β 0.078 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Cocaine
Levine, B. and Tebbett, I., "Cocaine pharmacokinetics in ethanol-pretreated rats", Drug
Metabolism and Disposition, Vol. 22, (1994), p. 498 - 500.
This study looks into several reports which claim that the euphoric effects of
cocaine can be enhanced when taken in conjunction with alcohol. This effect may be
the result of higher cocaine blood levels or a reduced elimination of cocaine or a
combination of both. Graph the data and find A1, α, B1, β. Check your answers with
the answers given below and answer the remaining questions using the correct
answers.
0.000 0.000 1.635
0.003 0.191 1.556
0.016 0.957 1.291
0.032 1.915 1.048
0.064 3.830 0.754
0.096 5.744 0.607
15.403 924.196 0.231
30.807 1848.392 0.116
46.210 2772.589 0.058
77.016 4620.981 0.014
115.525 6931.472 0.003
Weight of rat
Dose 2 mg/kg cocaine
(also 1 g/ kg ethanol)
ng
A1 1172.6
mL
α 0.362 min −1
ng
B1 462
mL
β 0.045 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
1,2-Diethyl-3-Hydroxypyridine-4-One
Epemolu, O., et al., "The pharmacokinetics of 1,2-Diethyl-3-Hydroxypyridine-4-One
(CP94) in rats, Drug Metabolism and Disposition, Vol. 20, (1992), p. 736 - 741.
1,2-Diethyl-3-Hydroxypyridine-4-One (CP94) is an iron chelator which is orally

active. It is being investigated for use in the treatment of hemoglobinopathic disorders.
In this study, rats weighing 250 - 300 g were given doses 50 mg /kg intravenously and
the following data was collected: Graph the data and find A1, α, B1, β. Check your
correct answers.
0.000 0.000 39.030
0.034 2.049 36.856
0.171 10.244 29.469
0.341 20.487 22.591
0.683 40.974 13.997
1.024 61.461 9.371
1.824 109.444 4.827
3.648 218.889 2.051
5.472 328.333 1.017
9.120 547.221 0.254
13.681 820.832 0.045
18.241 1094.443 0.008
Weight of rat 275 g
Dose 50 mg/kg IV
mg
A1 30.9
L
α 2.03 hr −1
mg
B1 8.13
L
β 0.38 hr −1
Assume that the rat ( which weighs 275 g) is suffering from thalassemia and his
iron levels are very high. The rat is prescribed CP94 to restore the iron levels to normal.
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
2,2-dimethylaziridine
Lalka, D., Jusko, W., and Bardos, T., "Reactions of 2,2-dimethylaziridine-type alkylating agents
in biological systems II: Comparative pharmacokinetics in dogs", Journal of Pharmaceutical
Sciences, Vol. 64, (1975), p. 230 - 235.
The 2,2-dimethylaziridine alkylating agents are used for their antitumor capability
as antineoplastic agents. In this study, male mongrel dogs, weighing 20 - 28 kg, were
each given a dose of 12 mg/kg of ethyl bis (2,2-dimethylaziridinyl) phosphinate
intraveneously. Graph the data and find A1, α, B1, β. Check your answers with the
answers given below and answer the remaining questions using the correct answers.
0.000 0.000 50.500
0.003 0.169 47.552
0.014 0.847 37.541
0.028 1.695 28.236
0.056 3.389 16.660
0.085 5.084 10.494
0.122 7.296 6.374
0.243 14.593 2.232
0.365 21.889 1.068
0.608 36.481 0.266
0.912 54.722 0.047
1.216 72.963 0.008
Weight of dog 24 kg
Dose 12 mg/kg IV
µg
A1 42
mL
α 0.409 min −1
µg
B1 8.5
mL
β 0.095 min −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Flurbiprofen
Menzel-Soglowek, S., et al., "Variability of inversion of (R)-flurbiprofen in different species",
Journal of Pharmaceutical Sciences, Vol. 81, (1992), p. 888 - 891.
Flurbiprofen is an anti-inflammatory and analgesic agent. This study compares

the pharmacokinetics of the (R)-isomer of flurbiprofen to the those of the (S)-isomer.
The following data was approximated from the graph given in this article. Graph the
data and find A1, α, B1, β. Check your answers with the answers given below and
answer the remaining questions using the correct answers.
0.000 0.000 107.180
0.030 1.785 103.627
0.149 8.925 91.467
0.297 17.849 79.953
0.595 35.699 65.003
0.892 53.548 56.258
3.961 237.650 29.345
7.922 475.301 14.670
11.883 712.951 7.335
19.804 1188.252 1.834
29.706 1782.378 0.324
39.608 2376.505 0.057
Weight of rat 260 g
Dose 10 mg/kg IV
mg
A1 48.5
L
α 2.33 hr −1
mg
B1 57.68
L
β 0.175 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Furosemide
Tilsone, W., and Fine, A., "Furosemide kinetics in renal failure", Clinical Pharmacology and
Therapeutics, Vol. 23, (1978), p. 644 - 650.
Furosemide is an agent which is used for its diuretic action to treat such
conditions as renal and cardiac edema. In this study, normal subjects were given an
intravenous bolus dose of 22 mg of furosemide. Blood samples were taken at various
intervals and the following data was obtained: Graph the data and find A1, α, B1, β.
Check your answers with the answers given below and answer the remaining questions
using the correct answers.
0.000 0.000 2.870
0.010 0.603 2.722
0.050 3.014 2.219
0.100 6.027 1.749
0.201 12.055 1.160
0.301 18.082 0.839
0.722 43.322 0.399
1.444 86.643 0.193
2.166 129.965 0.096
3.610 216.608 0.024
5.415 324.913 0.004
7.220 433.217 0.001
Dose 22 mg IV
mg
A1 2.1
L
α 6.9 hr −1
µg
B1 0.77
mL
β 0.96 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Glycyrrhizin
Tsai, T., et al., "Pharmacokinetics of glycyrrhyzin after intravenous administration to rats",
Journal of Pharmaceutical Sceinces, Vol. 81, (1992), p. 961- 963.
Glycyrrhizin is a component of licorice which is proposed to have anti-

inflammatory, anti-hepatotoxic, interferon-inducing, anti-viral, and anti-ulcer activity. It
also causes pseudoaldosteronism. The following data was approximated from the
graph given in this article. Graph the data and find A1, α, B1, β. Check your answers
answers.
0.000 0.000 161.130
0.017 1.000 154.522
0.083 4.999 131.950
0.167 9.997 110.682
0.333 19.995 83.376
0.500 29.992 67.784
1.612 96.718 35.062
3.224 193.436 17.475
4.836 290.155 8.738
8.060 483.591 2.184
12.090 725.387 0.386
16.120 967.182 0.068
Weight of rat 275 g
Dose 20 mg/kg
mg
A1 91.23
L
α 4.16 hr −1
µg
B1 69.90
mL
β 0.43 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Human Deoxyribonuclease
Mohler, M., et al., "Altered pharmacokinetics of recominant human deoxyribonuclease in rats due to the
presence of a binding protein", Drug Metabolism and Disposition, Vol. 21, (1993), p. 71 - 75.
Deoxyribonucleases are found in human serum, urine, and a variety of tissues.

These endonucleases catalyze the hydrolysis of DNA to oligonucleotides. It has been
suggested that increased levels of serum deoxyribonucleases may predict
malignancies. Graph the data and find A1, α, B1, β. Check your answers with the
0.000 0.000 24147.000
0.008 0.483 22848.865
0.040 2.415 18463.873
0.081 4.830 14432.548
0.161 9.661 9532.230
0.242 14.491 7039.766
3.027 181.611 2448.500
6.054 363.221 1224.250
9.081 544.832 612.125
15.134 908.053 153.031
22.701 1362.080 27.052
30.268 1816.106 4.782
Patient weight 260 g
Dose 1 mg/kg IV bolus
mg
A1 19250
L
α 8.61 hr −1
ng
B1 4897
mL
β 0.229 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Human Granulocyte Colony-Stimulating Factor
Tanaka, H., and Kaneko, T., "Pharmacokinetic and pharmacodynamic comparisons between human
granulocyte colony-stimulating factor purified from human bladder carcinoma cell line 5637 culture
medium and recombinant human granulocyte colony-stimulating factor produced in Escherichia coli", The
Journal of Pharmacology and Experimental Therapeutics, Vol. 262, (1992), p. 439 - 444.
Human Granulocye Colony-Stimulating Factor (hG-CSF) is used to stimulate the

proliferation of precursor cells and their subsequent differentiation in the bone marrow.
This article compares the pharmacokinetics of hG-CSF produced by two different
methods. In the first method, the hG-CSF was obtained from human bladder carcinoma
cell line 5637 culture medium. In the second method, the hG-CSF was produced by
Escherichia coli. Graph the data and find A1, α, B1, β. Check your answers with the
0.000 0.000 116.309
0.024 1.440 108.526
0.120 7.200 82.266
0.240 14.400 58.192
0.480 28.800 29.129
0.720 43.200 14.593
1.270 76.200 3.016
2.540 152.400 0.101
3.810 228.600 0.014
6.350 381.000 0.003
9.525 571.500 0.001
Weight of rat 250 g
Dose 10 µg/kg IV
mg
A1 116.21
L
t 12 ( α ) 0.24 hours
ng
B1 99.228
mL
t 12 ( β ) 1.27 hours
1. What is AUCα ?
2. What is AUCβ ?
7. What is α?
8. What is β?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Hydrocortisone
Derendorf, H., et al., "Pharmacokinetics and oral bioavailability of hydrocortisone",
Journal of Clinical Pharmacology, Vol. 31, (1991), p. 473 - 476.
This study looks at both the two-compartment model pharmacokinetics and the
oral bioavailability of hydrocortisone. The following data was approximated from the
graph given in this article. Graph the data and find A1, α, B1, β. Check your answers
answers.
0.000 0.000 869.000
0.005 0.317 839.172
0.026 1.587 737.918
0.053 3.175 643.784
0.106 6.349 526.306
0.159 9.524 462.810
1.558 93.458 219.500
3.115 186.916 109.750
4.673 280.374 54.875
7.788 467.290 13.719
11.682 700.935 2.425
15.576 934.580 0.429
Dose 20 mg IV
mg
A1 430
L
α 13.1 hr −1
µg
B1 439
mL
β 0.445 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Levodopa
Sasahara, K., et al., "Dosage form design for improvement of bioavailability of levodopa II:
Bioavailability of marketed levodopa preparations in dogs and parkinsonian patients" Journal of
Pharmaceutical Sciences, Vol. 69, (1980), p. 261 - 265.
Levodopa is an agent used in the treatment of Parkinson's disease. This study

looks at various dosage forms of levodopa and compares the pharmacokinetic
parameters of each. The following data was approximated from the graph given in this
article. Graph the data and find A1, α, B1, β. Check your answers with the answers
given below and answer the remaining questions using the correct answers.
0.000 0.000 11.600
0.005 0.313 11.004
0.026 1.563 8.985
0.052 3.127 7.114
0.104 6.254 4.795
0.156 9.381 3.564
0.608 36.481 1.488
1.216 72.963 0.743
1.824 109.444 0.371
3.040 182.407 0.093
4.560 273.611 0.016
6.080 364.814 0.003
Dose 50 mg IV
mg
A1 8.63
L
α 13.3 hr −1
µg
B1 2.97
mL
β 1.14 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Meropenem
Chimata, M., et al., "Pharmacokinetics of meropenem in patients with various degrees of renal
function, including patients with end-stage renal disease", Antimicrobial Agents and
Chemotherapy, Vol. 37, (1993), p. 229 - 233.
Meropenem is a carapenem antibiotic which has a broad spectrum of activity. It

is used in the treatment of infections caused by both Gram-positive and Gam-negative
bacteria and is active against Enterobacteriaceae and Pseudomonas aeruginosa.
Meropenem is 60% renally and 40% hepatically eliminated. Answer the remaining
questions using the analysis given.
0.000 0.000 41.000
0.037 2.248 39.220
0.187 11.240 33.051
0.375 22.480 27.065
0.749 44.961 18.969
1.124 67.441 13.988
1.378 82.682 11.641
2.756 165.363 5.128
4.134 248.045 2.510
6.890 413.408 0.625
10.335 620.112 0.110
13.780 826.816 0.020
Dose 500 mg IV infusion over 40
minutes
mg
A1 21
L
α 1.85 hr −1
µg
B1 20
mL
β 0.503 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
N-Methylpyridinium-2-Carbaldoxime Chloride
Bodor, N., and Brewster, M., "Problems of delivery of drus to the brain", International
Encyclopedia of Pharmacology and Therapeutics, Vol. 120, (1975)
N-methylpyridinium-2-cabaldoxime chloride (2-PAM) is the drug of choice for the

treatment of orgaonphosphate poisoning. It is mostly renally excreted. This article
considers the fact that this agent is highly hydrophilic and thus has difficulty reaching
the brain. The following data was approximated from the graph given in this article.
Graph the data and find A1, α, B1, β. Check your answers with the answers given
below and answer the remaining questions using the correct answers.
0.000 0.000 41.339
0.060 3.59 23.256
0.120 7.179 14.170
0.179 10.769 9.584
0.241 14.443 7.210
0.299 17.948 6.038
0.449 26.922 4.906
0.598 35.896 4.544
1.204 72.213 3.787
2.407 144.426 2.678
Weight of dog 40 kg
Dose 7.0 mg/kg
mg
A1 5.356
L
α 0.28796 hr −1
mg
B1 35.983
L
β 11.586 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Pyrazine Diazohydroxide
Vogelzang, N., et al., "Phase I and pharmacokinetic study of a new antineoplastic agent: pyrazine
diazohydroxide (NSC 361456)", Journal of Cancer Research , Vol. 54, (1994), p. 114 - 119.
Pyrazine diabhohydroxide is an agent which forms a reactive pyrazine dizonium

ion in vivo which acts to destroy tumor cells. This study looks at the pharmacokinetic
parameters of this agent in advanced cancer patients whose cancer was not curable by
any other type of therapy. They were given a dose of 18 mg/m2/day for 5 days every 4
weeks. Most of the following data was collected for a 66 year old male subject. The
remaining data was approximated from the graph given in this article. Graph the data
and find A1, α, B1, β. Check your answers with the answers given below and answer
the remaining questions using the correct answers.
0.000 0.000 9249.000
0.006 0.355 8698.260
0.030 1.777 6834.448
0.059 3.555 5113.957
0.118 7.109 3003.703
0.178 10.664 1909.575
0.450 26.971 634.920
0.899 53.941 296.718
1.349 80.912 148.251
2.248 134.854 37.063
3.371 202.280 6.552
4.495 269.707 1.158
Patient Body Surface 1.82 m2
Area
Dose 18 mg/ m2
µg
A1 8063
mL
α 0.195 min −1
µg
B1 1186
mL
β 0.0257 min −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Rhizoxin
Graham, M., et al., "Preclinical and phase I studie with rhizoxin to apply a pharmacokinetically
guided dose-escalation scheme", Journal of the National Cancer Institute, (1991), p. 494 - 499.
Rhizoxin is a lactone which was obtained from the fungus, Rhizopus chinensis. It
has anti-tumor activity against a broad spectrum of tumor types including LOX
melanoma, A549 lung tumors, and MX-1 mammary tumors. This study looks at dosing
of rhizoxin. Patients with nontreatable tumors who had a life expectancy of more than
12 weeks were given doses of 12 mg/ m2. The following data was approximated from
the graph given in this article. Graph the data and find A1, α, B1, β. Check your
correct answers.
Time(hr)Time(min) Cp(µMol/mL)
0.000 0.000 1.670
0.017 1.040 1.566
0.087 5.199 1.215
0.173 10.397 0.893
0.347 20.794 0.503
0.520 31.192 0.307
5.975 358.524 0.060
11.951 717.049 0.030
17.926 1075.573 0.015
29.877 1792.622 0.004
44.816 2688.933 0.001
Patient Body Surface 1.82 m2
Area
Dose 12 mg/ m2
µM
A1 1.55
mL
α 4.00 hr −1
µM
B1 0.12
mL
β 0.116 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Terbinafene
Kovarik, J., et al., "Dose-proportional pharmacokinetics of terbinafine and its N-demethylated
metabolite in healthy volunteers", British Hournal of Dermatology, Vol. 126, (1992), p. 8 - 13.
Terbinafene is an antifungal agent which acts by interfering with ergosterol

biosynthesis. It is active against Trichophyton, Epidermophyton, and Microsporum.
Approximately 70% of an oral dose is absorbed. Terbinafene has an N-demethylated
metabolite which is active. The following data was approximated from the graph given
in this article. Graph the data and find A1, α, B1, β. Check your answers with the
0.000 0.000 2.500
0.136 8.139 2.339
0.678 40.694 1.796
1.356 81.387 1.298
2.713 162.774 0.696
4.069 244.161 0.393
31.223 1873.371 0.051
62.446 3746.742 0.026
93.669 5620.112 0.013
156.114 9366.854 0.003
Dose 750 mg
ng
A1 2398
mL
α 0.511 hr −1
ng
B1 102
mL
β 0.0222 hr −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Verrucarol
Barel, S., Yagen, B., and Bailer, M., "Pharmacokinetics of the trichothecen mycotoxin verrucarol
in dogs", Journal of Pharmacetuical Seciences, Vol. 79, (1990), p. 548 - 550.
Verrucarol is a toxin which is related to toxins which have anti-tumor activity.

This study looks at the pharmacokinetics of verrucarol in dogs. The following data was
approximated from the graph given in this article. Graph the data and find A1, α, B1, β.
Check your answers with the answers given below and answer the remaining questions
using the correct answers.
0.000 0.000 0.667
0.028 1.670 0.650
0.139 8.351 0.589
0.278 16.702 0.525
0.557 33.405 0.426
0.835 50.107 0.352
1.221 73.271 0.276
2.442 146.543 0.135
3.664 219.814 0.068
6.106 366.357 0.017
9.159 549.535 0.003
Weight of Dog 22.5 kg
Dose 0.4 mg/ kg
ng
A1 126.05
mL
α 0.0415 min −1
ng
B1 540.58
mL
β 0.00946 min −1
1. What is AUCα ?
2. What is AUCβ ?
7. What is t 1 2 (α ) ?
8. What is t 1 2 ( β ) ?
9. What is k21 ?
10. What is k10 ?
11. What is k12 ?
13. What is Cpo ?
Answers
Aspirin Caffeine Ceftazidime Cocaine

1. 8.019 µg ⋅min 1. 2.15 µg ⋅ h 1. 22.87 mg ⋅ h 1. 3239.2 ng ⋅ min
mL mL L mL
2. 36.2 µg ⋅ min 2. 39.57 µg ⋅ h 2. 118.78 mg ⋅ h 2. 10266.7 ng ⋅ min
mL mL L mL
3. 31.1 mL 3. 41.72 µg ⋅ h 3. 141.65 mg ⋅ h 3. 13505.89
min mL L ng ⋅ min
mL
4. 2.62 minutes 4. 7.67 L 4. 7.0598 L 4. 44.43 mL
h h min
5. 155.48 mL 5. 33.35 L 5. 14.41 L 5. 987.2 mL
6. 86.92 mL 6. 16.28 L 6. 4.06 L 6. 367.1 mL
7. 81.57 mL 7. 0.141 hours 7. 0.0843 hours 7. 1.91 minutes
8. 0.648 min 8. 3.014 hours 8. 1.415 hours 8. 15.4 minutes
9. 3.47 min 9. 2.39 h-1 9. 2.32 h-1 9. 0.1346 min-1
10. 0.598 min-1 10. 0.471 h-1 10. 1.738 h-1 10. 0.1210 min-1
11. 0.358min-1 11. 2.266 h-1 11. 4.65 h-1 11. 0.1514 min-1
12. 0.314min-1 12. 19.65 µg 12. 246.2 mg 12. 1634.6 ng
mL L mL
13. 15.82 µg 13. 0.655 hours 13. 0.365 hours 13. 8.35 minutes
mL
14. 1.928 minutes 14. 51.2% 14. 39.2% 14. 59.2%
15. 44.1% 15. Yes 15. Yes 15. No
16. Yes
17. 0.381 min-1

Buprenorphine Cefazolin Clentiazem 1,2-Diethyl-3-hydroxpyridine-4-
one
1. 10.54 ng ⋅ h 1. 42.73 µg ⋅ h 1. 13.9 ng ⋅ h 1. 15.22 mg ⋅ h

mL mL mL L
2. 36.9 ng ⋅ h 2. 214.59 µg ⋅ h 2. 207.3 ng ⋅ h 2. 21.39 mg ⋅ h
mL mL mL L
3. 47.4 ng ⋅ h 3. 257.32 µg ⋅ h 3. 221.2 ng ⋅ h 3. 36.62 mg ⋅ h
mL mL mL L
4. 366.8 mL 4. 3.89 L 4. 90.4 L 4. 375.5 mL
h h h h
5. 2.85 hours 5. 6.78 L 5. 1159.2 L 5. 988.2 mL
6. 1.35 L 6. 3.035 L 6. 372.5 L 6. 352.3 mL
7. 0.34 L 7. 0.143 hours 7. 0.257 hours 7. 0.341 hours
8. 0.178 hours 8. 1.21 hours 8. 8.89 hours 8. 1.824 hours
9. 2.58 hours 9. 2.163 h-1 9. 0.868 h-1 9. 0.724 h-1
10. 0.981 h-1 10. 1.28 h-1 10. 0.243 h-1 10. 1.066 h-1
11. 1.075 h-1 11. 1.96 h-1 11. 1.67 h-1 11. 0.62 h-1
12. 2.11 h-1 12. 329.44 µg 12. 53.69 ng 12. 39.03 mg
mL mL L
13. 51 ng 13. 0.50 hours 13. 1.35 hours 13. 1.016 hours
mL
14. 0.736 hours 14. 55.2% 14. 47.4% 14. 55.4%
15. No
15. 74.9% 15. Yes 15. Yes
16. No
17. Can't be calc
2,2-dimethylaziridine Furosemide Human Hydrocortisone
Deoxyribonuclease
1. 102.7 µg ⋅ min 1. 0.304 mg ⋅ h 1. 2235.78 ng ⋅ h 1. 32.8 mg ⋅ h
mL L mL L
2. 89.47 µg ⋅ min 2. 0.802 mg ⋅ h 2. 21384.3 ng ⋅ h 2. 986.5 mg ⋅ h
mL L mL L
3. 192.16 µg ⋅ min 3. 1.106 mg ⋅ h 3. 23620.1 ng ⋅ h 3. 1019.3 mg ⋅ h
mL L mL L
4. 1498.7 mL 4. 19.88 L 4. 11.01 mL 4. 19.62 mL
min h h h
5. 15.78 L 5. 20.71 L 5. 48.07 mL 5. 44.1 mL
6. 5.7 L 6. 7.67 L 6. 10.77 mL 6. 23.01 mL
7. 1.695 minutes 7. 0.1005 hours 7. 0.0805 hours 7. 0.053 hours
9. 0.148 min-1 9. 2.55 h-1 9. 1.929 h-1 9. 6.838 h-1

10. 0.263 min-1 10. 2.59 h-1 10. 1.0223 h-1 10. 0.853 h-1
11. 0.093 min-1 11. 2.71 h-1 11. 5.89 h-1 11. 5.85 h-1
12. 50.5 µg 12. 2.87 mg 12. 24147 ng 12. 869 mg
mL L mL L
14. 56.5% 14. 62.99% 14. 28.9% 14. 47.8%
15. No 15. No 15. Yes 15. Yes
Flurbiprofen Glycyrrhizin Human Granulocyte Levodopa

Colony-Stimulating
Factor
1. 20.82 mg ⋅ h 1. 21.93 mg ⋅ h 1. 40.24 ng ⋅ h 1. 0.649 mg ⋅ h
L L mL L
2. 329.6 mg ⋅ h 2. 162.56 mg ⋅ h 2. 181.81 ng ⋅ h 2. 2.61 mg ⋅ h
L L mL L
3. 350.42 mg ⋅ h 3. 184.5 mg ⋅ h 3. 222.05 ng ⋅ h 3. 3.25 mg ⋅ h
L L mL L
4. 7.42 mL 4. 29.8 mL 4. 11.26 mL 4. 15.37 L
h h h h
5. 42.4 mL 5. 69.33 mL 5. 20.62 mL 5. 13.48 L
6. 24.5 mL 6. 34.13 mL 6. 11.6 mL 6. 4.31 L
7. 0.297 hours 7. 0.167 hours 7. 2.89 h-1 7. 0.052 hours
8. 3.96 hours 8. 1.61 hours 8. 0.546 h-1 8. 0.61 hours
9. 1.35 h-1 9. 2.048 h-1 9. 1.625 h-1 9. 4.25 h-1

10. 0.303 h-1 10. 0.873 h-1 10. 0.971 h-1 10. 3.56 h-1
11. 0.856 h-1 11. 1.67 h-1 11. 0.839 h-1 11. 6.62 h-1
12. 106.18 mg 12. 161.13 mg 12. 215.44 ng 12. 11.6 mg
L L mL L
13. 1.2 hours 13. 0.61 hours 13. 0.711 hours 13. hours
14. 42.2% 14. 50.8% 14. 43.8% 14. 68.0%
15. Yes 15. Yes 15. Yes 15. Yes
Meropenem Pyrazine Diazohydroxide Verrucarol
1. 11.35 mg ⋅ h 1. 41348.7 1. 3037.35 ng ⋅ min
L µg ⋅ min mL
mL
2. 39.76 mg ⋅ h 2. 46147.9 2. 57143.8
L µg ⋅ min ng ⋅ min
mL mL
3. 51.11 mg ⋅ h 3. 87496.6 3. 60181.1 ng ⋅ min
L µg ⋅ min mL
mL
4. 9.78 L 4. 0.3744 mL 4. 149.5 mL
h min min
5. 19.45 L 5. 14.57 mL 5. 15.81 L
6. 12.20 L 6. 3.542 mL 6. 13.5 L
7. 0.375 hours 7. 3.55 minutes 7. 16.7 minutes
9. 1.16 h-1 9. 0.0474 min-1 9. 0.0155 min-1

10. 0.802 h-1 10. 0.106 min-1 10. 0.0253 min-1
11. 0.391 h-1 11. 0.0676 min-1 11. 0.0101 min-1
12. 41 mg 12. 9249 µg 12. 666.63 ng
L mL mL
14. 37.3% 14. 75.7% 14. 28.1%
15. No 15. No 15. Yes
N-methylpyridinium-2- Terbinafene
carbaldoxime chloride
1. 18.6 mg ⋅ h 1. 4692.8 ng ⋅ h
L mL
2. 3.106 mg ⋅ h 2. 4594.6 ng ⋅ h
L mL
3. 21.71 mg ⋅ h 3. 9287.4 ng ⋅ h
L mL
4. 12.9 L 4. 80.75 L
h h
5. 1.11 L 5. 3637.6 L
6. 6.77 L 6. 300 L
7. 2.41 hours 7. 1.36 h
8. 0.0598 hours 8. 31.2 h
9. 1.752 h-1 9. 0.0421 h-1

10. 1.905 h-1 10. 0.2692 h-1
11. 8.218 h-1 11. 0.222 h-1
12. 41.339 mg 12. 2500 ng
L mL
13. 0.327hours 13. 6.42 hours
?14. 45.5% 14. 91.8%
15. Yes 15. No
CHAPTER 12 Protein Binding

OBJECTIVES
2.

Non-Linear Pharmacokinetics
Non-linear pharmacokinetic models, as opposed to linear pharmacokinetic models differ
in some very critical areas. When the concentration that results from the dose is
proportional to that dose and the rate of elimination of the drug is proportional to the
concentration, the drug is said to exhibit linear pharmacokinetics as shown below.
Figure 13-1-1 Figure 13-1-2

30
100
25
75
20
Cp (ng/mL)
Cp (ng/mL)
15 50
10
25
5
0 0
0 5 10 15 20 25 30
0 5 10 15
Dose (mg) Time (hr)
Dose
Cp ∝ Dose = (13.1.1)
Volume
∂Cp
− ∝ Cp (13.1.2)
∂Time
Integrating equation (13.1.2) results in the first order equation:

Cp = Cp0 e − KT (13.1.3)
which can be rewritten to
LN (Cp) = LN (Cp0 ) − KT (13.1.4)
A graph of which is linear with time as shown below.
Figure 13-1-3
100
Cp (ng/mL)
10
1
0 5 10 15 20 25 30
Time (hr)
When concentration that results from the dose is not proportional to that dose and/or the
rate of elimination of the drug is not proportional to the concentration, the drug is said to
exhibit non-linear kinetics as shown below.
Figure 13-1-5
Figure 13-1-4
1000
100
900
90
800
80
Cp (ng/mL) ave
70 700
Cp (ng/mL)
60 600
50 500
40 400
30
300
20
200
10
100
0
0
0 100 200 300 400 500 0 10 20 30 40
Dose/day Time (hours)
If we were to plot LN(Cp) vs Time as in figure (13.1.4), we would observe the following:
Figure 13-1-6
1000
100
Cp (ng/mL)
10
1
0 10 20 30 40
Time (hours)
Compare the terminal portion of the curve (time>25 hours) of figures 5 and 6 with figures
2 and 3. Looks similar, doesn’t it. Well, there’s a reason for it. In many cases, the rate
of elimination of the drug is defined by the enzymatic metabolism. From biochemistry,
we (should) remember the Michaelis-Menten equation that describes the rate of substrate
metabolism.
∂C V C
= − max (13.1.5)
∂t ( Km + C )
Where Vmax = the maximum velocity capable by the enzymes
Km = drug concentration that is metabolized at half the
maximum velocity
Drugs that exhibit this kind of behavior are said to exhibit non-linear pharmacokinetics.
Let’s look at the various portions of the curve. There are three distinct portions of this
curve:
1) The initial straight portion of the figure 13-1-5 (Cp >> Km)
2) The middle curved portion of figure 13-1-5 and 13-1-6 (Cp ≈ Km)
3) The terminal straight portion of figure 13-1-6 (Cp << Km)
If (Cp >> Km) then equation (13.1.5) becomes:

∂C V C
− max = −Vmax = − KC 0 (13.1.6)
∂t (C )
What we see is that the enzymatic activity is maxed out and the rate of elimination of the
drug is constant or, in math speak, the elimination rate is proportional to C to the zero
power. (Math review A0=1, Chapter 2.) Thus − KC 0 = − K . Drugs that exhibit this kind
of behavior are said to exhibit zero order behavior. The concentration is changed at a
constant rate, X mg/hour are removed by the metabolizing enzymes.
If (Cp << Km) then equation (13.1.5) becomes:

∂C V C
= − max = − KC1 (13.1.7)
∂t ( Km )
Vmax
where =K
( Km )
Drugs that exhibit this kind of behavior are said to exhibit first order behavior. The
concentration is changed at a rate proportional to the concentration, X%/hour is removed
by the metabolizing enzymes.
Note equation (13.1.7) is identical to equation (13.1.2). Thus, what we see for a majority
of drugs is that equations (13.1.3) and (13.1.4) describe their pharmacokinetics because
the enzymes in the body are very efficient in the drug’s removal and the therapeutic
concentrations are well below the drug’s Km.
If (Cp ≈ Km) then the whole equation must be used and not just the limits as shown
above.
Why is this important? Because for those drugs where this is occurring, unlike drugs that
exhibit linear kinetics, where a change in daily dose results in a proportional change in
plasma concentration, as in the initial portion of figure 13-1-4 (< 200 mg/day), a small
change in daily dose could result in a LARGE change in plasma concentration, as shown
in the terminal portion of figure 13-1-4 (> 400 mg/day). In other words something like a
10% change in dose would not yield a 10% change in concentration but could yield a
100% (or greater) change in concentration. This could lead to toxicity.
At steady state, the rate of drug being put into the body equals the rate of drug
being removed from the body by the enzymes, thus:
fD Vmax Cpss
RateIn = DailyDose = = = RateOut (13.1.8)
τ ( K m + Cpss )
where tau = one day.
Multiplying (13.1.8) by (Km+Cpss)

DD ⋅ Km+DD ⋅ Cpss =Vmax Cpss (13.1.9)
Where DD = Daily Dose
Divide (13.1.9) by Cpss

DD
K m + DD = Vmax (13.1.10)
Cpss
Rearanging (13.1.10)
DD
DD = Vmax − Km (13.1.11)
Cpss
And
mg
DD day Liter
= = = Clearance (13.1.12)
Cpss mg Day
Liter
So:
DD = Vmax − Clearance ⋅ K m (13.1.13)
Thus, the daily dose is proportional to the clearance, and a graph of Daily Dose vs.
Clearance will result in a straight line with an intercept of Vmax and a slope of - Km.
Example: Your patient is 90 Kg male and the doctor would like to achieve a Cpss of 18
mg/L of Phenytoin. Previously you patient received a dose of 400 mg/day Dilantin
Kapseals and attained a Cpss of 7.7 mg/L and a dose of 600 mg/day to attain a Cpss of
15.3 mg/L. Find Vmax, Km and the daily dose necessary to accieve the desired blood
level.
First of all Dilantin Kapseals are Sodium Phenytoin and must be converted to
Phenytion equivalents:
Molecular Weight of Sodium Phenytoin is 274.25 g/mole and the molecular
weight of Phenytoin is 252.27 g/mole. So, the daily dose of Phenytoin in each
case is calculated by:
MW Phenytoin
Mg Phenytoin = mg Phenytoin Sodium * (13.1.14)
MW Phenytoin Sodium
Where the Molecular Weight of Sodium Phenytoin is 274.25 g/mole and the
molecular weight of Phenytoin is 252.27 g/mole.
So: Converting Sodium Phenytoin to phenytoin using (13.1.15) and Calculating

clearance using (13.1.12) yields the following data:
Dosage Sodium Phenytoin Phenytoin Cpss Clearance

Regimen (mg/day) (mg/day) (mg/Liter) (L/day)
1 400 367.94 7.7 47.78
2 600 551.91 15.3 36.07
which can be graphically represented by:

Figure 13-1-7
y = -15.711x + 1118.6
600
500
Daily Dose (mg)
400
300
200
100
0
0 20 40 60
Clearance (L/ay)
The trend line yields a Km of 15.7 mg/L and a Vmax of 1118.6 mg/day. Plugging in the
values of Km and Vmax into equation (13.1.8)
Vmax Cpss 1118.6 mg day ⋅18 mg Liter

DailyDose = = (13.1.16)
( K m + Cpss ) 15.7 mg Liter + 18 mg Liter
we find that the daily dose needed to attain a Cpss of 18 mg/L of Phenytion is:
Daily Dose Daily Dose
(mg Phenytoin) (mg Sodium Phenytoin)
597.47 649.53
Whereas if the drug exhibitd linear kinetics and we wanted to increase the plasma
concentration from 15.3 mg/Liter to 18 mg/Liter the dose of Sodium Phenytion would be
= 705.88 mg. If we did dose our patient at this daily dose a further rearrangement of
equation (13.1.9) yields:
DD ⋅ K m
Cpss = (13.1.17)
Vmax − DD
Converting 705.88 mg of Sodium Phenitoin to Phenytoin yields 651.76 mg/Phenytoin.
Plugging that into equation (13.1.17) yields a plasma concentration of 21.92 mg/Liter
instead of the intended 18 mg/Liter. In other words, an 18% increase in dose
(652/552=1.18) yields a 44% increase in plasma concentration (22/15.3 = 1.44.) This
clearly could be a problem.
Problems:
Cefadroxil
Sanchez-Pico, A., et al, "Nonlinear intestinal abosrption kinetics of cefadroxil in
the rat", Journal of Pharmacy Pharmacology, Vol.41, (1989), p. 179 - 185.
Cefadroxil is a cephalosporin antibiotic which is commonly used to treat

various infections. It is usually given orally. This study looks at the
pharmacokinetics and bioavailability of cefadroxil in the rat.
Dose C pss
µg
500 mg 7.31
mL
µg
1000 mg 14.67
mL
1. Find km .
2. Find the maximum clearance, v max , for this patient.
3. What would be the dose needed to acheive a steady-state concentration of

µg
10 ?
mL
4. You recommend changing the patient's dosage regimen to 300 mg/day.

What would be your patient's steady state plasma concentration?
CD4
Qian, M., et al., "Pharmacokinetic evaluation of drug interactions with anti-human
immunodeficiency virus drugs: V. effect of soluble CD4 on 2',3'-dideoxycytidine
kinetics in monkeys", Drug Metabolism and Disposition, Vol. 20, (1992), p. 396 - 400.
2',3'-dideoxycytidine in combination with recombinant ST4 has been

shown to be effective against HIV (human immunodeficiency virus) in vitro. This
study examines whether or not the pharmacokinetics of 2',3'-dideoxycytidine are
affected by administration of CD4 (an immunoglobulin). Doses of each drug
were given to male adult monkeys weighing an average of 4.45 kg. The
following data is for ST4 (soluble CD4).
Dose C pss
µg
1.1 mg/kg 10.27
mL
µg
2.2 mg/kg 22.23
mL
Weight of Monkey = 4.45 kg
1. Find km .

µg
15 ?
mL
4. You recommend changing the patient's dosage regimen to 1.5 mg/ kg.
What would be your patient's plasma concentration?
Methylprednisone
Haughey, D, and Jusko W.., "Bioavailability and nonlinear dispositionof methylprednisolone and
methylprednisone in the rat", Journal of Pharmaceutical Sceicnes, Vol. 81, (1992), p. 117 - 121.
Methylprednisone is a corticosteroid which is commonly used in the

treatment of medical emergencies such as cardiovascular shock, asthma, and
cerebral edema. The following data was obtained for two methylprednisolone
doses. The plasma concentration measurement given for each dose below is
that for the central compartment.
Dose C pss
ng
10 mg 6834
mL
nmol
50 mg 71519
L
1. Find km .

ng
10,000 ?
mL
4. You recommend changing the patient's dosage regimen to 30 mg. What

would be your patient's plasma concentration?
Mezlocillin
Jungbluth, G. and Jusko, W., "Dose-dependent pharmacokinetics of mezlocillin in
rats", Antimicrobial Agents and Chemotherapy, Vol. 33, (1989), p. 839 - 843.
Mezlocillin is an antibiotic used to treat various types of infection. It is

usually given by the intravenous route and exhibits dose-dependent (nonlinear)
pharmacokinetics. This article compares two intravenous bolus doses, one of 20
mg/kg and one of 200 mg/kg in rats. The following data was calculated from the
results of this study.
Dose C pss
µg
20 mg/kg 158.6
mL
µg
200 mg/kg 294.1
mL
Rat weight = 425 g
1. Find km .

µg
200 ?
mL
4. You recommend changing the patient's dosage regimen to 150 mg/ kg.
Naphthol
Redegeld, A., Hofman, G., and Noordhoek, J., "Conjugative clearance of 1-naphthol and
disposition of its glucuronide and sulfate conjugates in the isolated perfused rat",
Journal of Harmacology and Experimental Therapeutics, Vol. 244, (1988), p. 263 - 267.
1-naphthol is a small phenolic compound which is extensively metabolized

by conjugation. This study looks at the pharmacokinetics of naphthol in a rat.
Dose C pss
30 µmol 6.79 µM
40 µmol 8.63 µM
1. Find km .

7.7 µM?
4. You recommend changing the patient's dosage regimen to 35 µmol. What

Paroxetine
Sindrug, S., Brosen, K, and Gram, L.., "Pharmacokinetics of the selective serotonin reuptake
inhibitor paroxetine: nonlinearity and relation to the sprateine oxidation polymorphism", Clinical
Pharmacology and Therapeutics, Vol. 51, (1992), p. 288 - 295.
Paroxetine hydrochloride (Paxil) is a selective serotonin reuptake

inhibitor which is used in the treatment of depression. Paroxetine is metabolized
both by oxidation and conjugation with the conjugated metabolites excreted in
the urine. Paroxetine exhibits dose-dependent (nonlinear) pharmacokinetics.
The following data is for a male diabetic patient who was concurrently taking
insulin.
Dose C pss
ng
10 mg daily 1.65
mL
ng
20 mg daily 3.30
mL
ng
30 mg daily 8.25
mL
ng
40 mg daily 13.20
mL
ng
50 mg daily 26.40
mL
ng
60 mg daily 39.60
mL
ng
70 mg daily 66.00
mL
1. Find km .

µg
50 ?
mL

Phenytoin
Levine, M., et al., "Evaluation of serum phanyton monitoring in an acute
care setting", Therapeutic Drug Monitoring, Vol. 10, (1988)., p. 50 - 57.
Phenytoin is an agent which is commonly used in the treatment of

epilepsy. This drug exhibits nonlinear kinetics. Phenytoin is mainly eliminated
from the body by hepatic cytochrome P-450 metabolism. Several doses of
phenytoin were studied in patients and the data is summarized below:
Dose Day C pss

300 mg at bedtime mg
2 5.0
(started on day 1) L
200 mg BID mg
12 11.4
200 mg BID mg
49 21.5
1. Find km .

mg
15 ?
L

Phenytoin in the Critically Ill
Boucher, B. et al., "Phenytoin pharmacokinetics in critically ill trauma patients",
Clinical Pharmacology and Therapeutics, Vol. 44, (1988)., p. 675 - 683.

epilepsy. This drug exhibits nonlinear kinetics. This study looks at several doses
of phenytoin in severely ill trauma patients. The data given below is that
obtained for one male, 25 year-old, patient who weighed 85 kg.
Dose C pss
mg
615 mg/ day 10
L
mg
588 mg/day 8.5
L
1. Find km .

mg
12 ?
L
4. You recommend changing the patient's dosage regimen to 450 mg/ day.
What would be your patient's steady-state plasma concentration?
Phenytoin in Pediatrics
Bauer, L. and Blouin, R., "Phenytoin Michaelis-Menten pharmacokinetics in caucasian
paediatric patients", Clinical Pharmacokinetics, Vol. 8, (1989)., p. 545 - 549.

epilepsy. This drug exhibits nonlinear kinetics. This study looks at several doses
of phenytoin in pediatric patients of several ages. The data for the 4 to 6 year old
patients is given below.
Dose C pss
µg
7.5 mg/ kg/ day 15
mL
µg
6.5 mg/ kg/day 10
mL
1. Find km .

mg
12 ?
L
4. You recommend changing the patient's dosage regimen to 4.5 mg/ kg/ day.
What would be your patient's steady-state plasma concentration?
Quinalapril
Elliott, H., et al., "Dose responses and pharmaockinetics for the angiotensin converting enzyme
inhibitor, quinapril", Clinical Pharmacology and Therapeutics, Vol. 52, (1992), p. 260 - 265.
Quinalapril is an angiotensin converting enzyme (ACE) inhibitor which is

used in the treatment of hypertension and heart failure. The optimal dosage
regimen for the ACE inhibitors is controversial and this study further investigates
quinalapril's pharmacokinetics at various doses ranging from 0.5 to 20 mg.
Quinalapril is a prodrug which is metabolized to its active form, quinalaprilat.
Dose C pss
(of quinalapril) (of quinalaprilat)
ng
2.5 mg daily 47.5
mL
ng
5.0 mg daily 98.1
mL
1. Find km .

ng
75 ?
mL
4. You recommend changing the patient's dosage regimen to 3.0 mg/day.

Vanoxerine
Ingwersen, S., et al., "Nonlinear multiple-dose pharmacokinetis of the dopamine reuptake
inhibitor vanoxerine", Journal of Pharmaceutical Sciences, Vol. 82, (1993)., p. 1164 - 1166.
Vanoxerine is a pre-synaptic dopamine reuptake inhibitor which may be

useful as an antidepressant. The bioavailability of vanoxerine is changed by food
intake. The bioavailability after fasting is increased 76% by a low-fat meal and
255% by a high-fat meal. In this study, the volunteers were given doses of
vanoxerine after eating a standard breakfast of one bowl of cereal with milk, two
slices of toast with sunflower margarine and jam, and one cup of tea.
Dose C pss
nmol
25 mg 3.4
L
nmol
75 mg 15.1
L
nmol
125 mg 46.5
L
1. Find km .

nmol
30.0 ?
L
4. You recommend changing the patient's dosage regimen to 100 mg. What
Nonlinear Equations
The following equations were used to solve the questions following

each "nonlinear" scenario. Three scenerios have been completed for
you. The answers have been provided for the remainder.
1.
D1 − D2
km =
D1 D2
ss
− ss
Cp Cp
1 2
Where:
D = Dose
Cpss = Steady - state plasma concentration
2.
Vmax =
(
D km + Cpss )
Cpss
Where:
Vmax = maximum clearance
km = Michaelis - Menten Rate Constant
Vmax ⋅ Cpss
3. D=
km + Cpss
D ⋅ km
4. Cpss =
Vmax − D
Phenytoin in the Critically Ill
D1 − D2 615 mg − 588 mg mg
1. km = = = 3.517
D1 D2 615 mg 588 mg L
− ss −
Cpss
Cp mg mg
1 2
10 8.5
L L
 mg mg 
2. Vmax =
(
D km + Cpss ) = 615 mg  3.517 L
+ 10 
L 
= 831.3 mg
Cpss mg
10
L
mg
Vmax ⋅ Cpss . mg ⋅ 10
8313
3. D= = L = 642.88 mg
km + Cpss mg mg day
3.517 + 10
L L
mg
D ⋅ km 450 mg ⋅ 3.517
4. Cpss = = L = 4.15 mg
Vmax − D 8313. mg − 450 mg L
________________________________________________________________
_____
CD4
1. The monkeys had an average weight of 4.45 kg.
mg
D1 = 2.2 • 4.45 kg = 9.79 mg
kg
mg
D1 = 11
. • 4.45 kg = 4.895 mg
kg
µg mg
Cpss = 22.23 = 22.23
1 mL L
ss µg mg
Cp = 10.27 = 10.27
2 mL L
D − D2 9.79 mg − 4.895 mg mg
km = 1 = = 135.09
D1 D2 9.79 mg 4.895 mg L
− ss −
Cp ss
Cp mg mg
1 2
22.23 10.27
L L
 mg mg 
2. Vmax =
(
D km + Cpss
=
)
9.79 mg  135.09
 L
+ 22.23 
L 
= 69.28 mg
Cpss mg
22.23
L
µg mg
3. Cpss = 15 = 15
mL L
mg
Vmax ⋅ Cpss 69.28 mg ⋅ 15 mg
D= = L = 6.92
km + Cpss mg mg day
135.09 + 15
L L
mg
4. D = 15
. • 4.45 kg = 6.675 mg
kg
mg
D ⋅ km 6.675 mg ⋅ 135.09
Cpss = = L = 14.40 mg
Vmax − D 69.28 mg − 9.79 mg L
_____________________________________________________________________
Cefadroxil
µg mg
1. Cpss = 14.67 = 14.67
1 mL L
µg mg
Cpss = 7.31 = 7.31
2 mL L
D1 − D2 1000 mg − 500 mg mg
km = = = 2144.75
D1 D2 1000 mg 500 mg L
− ss −
Cpss
Cp mg mg
1 2
14.67 7.31
L L
 mg mg 
2. Vmax =
(
D km + Cpss
=
)
500 mg  2144.75
 L
+ 7.31 
L 
= 147200 mg = 147.2 g
Cpss mg
7.31
L
µg mg
3. Cpss = 10 = 10
mL L
mg
Vmax ⋅ Cpss 147200 mg ⋅ 10 mg
D= = L = 683.14
km + Cpss mg mg day
2144.75 + 10
L L
mg
D ⋅ km 300 mg ⋅ 2144.75
4. Cpss = = L = 4.38 mg
Vmax − D 147200 mg − 300 mg L
Answers
Cefadroxil Phenytoin
1. 2144.75 µ g
mL 1. 4.014 µ g
mL
2. 147.2 g/day
3. 683.14 mg 2. 540.85 mg/day
3. 426.7 mg/day
4. 4.38 µ g
mL 4. 5 µg
mL
CD4 Phenytoin in the

1. 135.09 µ g
mL
Critically Ill
2. 69.28 mg/day 1. 3.517 µ g
3. 6.92 mg/day mL
4. 14.4 µ g 2. 831.3 mg/day
mL 3. 642.88 mg/day
4. 4.15 µ g
Methylprednisone mL
1. 52345.27 ng
mL
Phenytoin in
2. 86.60 mg/day Pediatrics
3. 13.89 mg/day
1. 6.67 µ g
4. 27747.1 ng mL
mL
2. 162.5 mg/day
3. 104.46 mg/day
Mezlocillin
4. 4.74 µ g
mL
1. 324.95 µ g
mL
2. 25.92 mg/day Quinalapril
3. 68.23 mg/day
1. 1503.15 ng
4. 1676.04 µ g mL
mL
2. 81.61 mg/day
3. 3.88 mg/day
Naphthol
4. 57.36 ng
1. 46.14 µM mL
2. 233.86 µmol
3. 25.61 µmol Vanoxerine
4. 43.5 µM
1. 20.96 nm ol
L
Paroxetine 2. 179.08 mg/day
3. 105.4 mg/day
1. 4.125 ng
mL 4. 26.5 nm ol
2. 45 mg/day L
3. 41.6 mg/day
4. 16.5 ng
mL
CHAPTER 14 Practice Exams: Section 1

Reviewer: Vicki Long
ORGANIZATION
Following are several exams which have been used
in previous classes. These exams cover Chapters 1
through 4. Answers (including the graphs) are
included in a format similar to real exam conditions,
and some exams have the problems worked out
completely.
You are encouraged to work out the exams under

conditions similar to how you will take the exam.
You will want to have a calculator, semi-log graph
paper, and scratch paper available. Before you
begin to answer the questions, you will want to: 1)
create the model from the description of the drug’s
pharmacokinetics, 2) graph all of the data as dis-
cussed in the chapters. From these graphs the
answers will become available. Your graphs should
look like the graphs included in the answers. Appli-
cable equations vary by exam and are included at the
beginning of each chapter covered by the exam.
Remember where you are in the course: Learn the
tools; get the pharmacokinetic parameters from
patient information. So in this section you must be
able to analyze pharmacokinetic data and extract the
pharmacokinetic parameters. That means: Assess
the pharmacokinetic description of the drug and cre-

Practice Exams: Section 1
ate a model, develop equations for the model, graph

the data according to those equations, and get the
parameters out. A student commented, “You mean,
all we have to do is get the slope and intercept from
a couple of graphs and tell you what they mean?”
Yes, that right!
Do not just look at the graphs and the answers and

say, “Yes, that makes sense. I can do this.” You will
be surprised to find out that what looks easy worked
out is not so easy when it isn’t.

Practice Exams: Section 1 : Nifedipine - Section 1
14.1 Nifedipine - Section 1

Masotti et al (J Clin Pcol 1985; 25: 27-35) and Traube et al (ibid 125-9) looked at the hemodynamic pharmacological response of
nifedipine.
14.1.1 NIFEDIPINE DATA

Nifedipine (Procardia ®) is a calcium channel blocker which specifically inhibits potential-dependent channels not
receptor-operated channels, preventing calcium influx of cardiac and vascular smooth muscle (coronary, cerebral).
Calcium channel blockers reduce myocardial contractility and A-V node conduction by reducing the slow inward cal-
cium current. They are indicated in angina, cardiac dysrhythmias, and hypertension among others. Nifedipine
appears to be metabolized entirely into an inactive metabolite, an acid and subsequently further metabolized to a lac-
tone. Both the acid and the lactone are excreted into the urine and the feces.
PROBLEM TABLE 11 - 1. Pharmacological Data
Fall in Diastolic Fall in Diastolic

BP Cp (ng/mL) Time (hr) BP
8 15 1 13.0
10 40 2 12.3
12 100 4 10.7
13 200 5 10.0
9 7.0
Echizen and Eichelbaum (Clin Pkin 1986; 11:425-49) and Kleinbloesem et al (Clin Pcol Therap 1986; 40: 21-8)
reviewed the pharmacokinetics of Nifedipine. While the drug is not routinely given by IV bolus and does not strictly
conform to a one compartment model, let's treat the data as if those problems can be ignored. The following data is
offered for evaluation:
PROBLEM TABLE 11 - 1. Nifedipine IV Bolus Profile
Cp Cm1 Xm1f Xm1u Xm2f Xm2u

Time (hr) (mcg/L) (mcg/L) (mg) (mg) (mg) (mg)
0.5 24.7
1 44.4
2 139 71.8 .14 .59
4 65.6 96.5 .44 1.83 .028 .11
6 31.1 100 .77 3.25 .073 .29
8 14.6 94.7 1.1 4.65 .135 .54
12 76.5 1.69 7.10 .291 1.15
24 34 2.77 11.63 .75 2.95
7 days 3.6 15.1 1.3 5.0

Copyright © 1996 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
14.1.2 NIFEDIPINE QUESTIONS

1) dR/dT = slope of the Pharmacological 18) AUMCiv = Area under the first moment
response vs. time profile (mmHg/hr) of the plasma concentration of Nifedipine vs
time curve of IV dose (mic/L*hr2 )
2) dR/d(lnC) = slope of the Pharmacolog-
ical response vs concentration profile 19) MRTiv = Mean Residence time of
(mmHg) Nifedipine given as the IV dose (hr)
3) d(lnC)/dt = slope of the concentration 20) Xm10 = Mass of acidic metabolite in
vs time profile (hr-1 ) the body at time = 0 (mg)
4) kr = rate constant of excretion of Nife- 21) Xm1inf = Mass of the acidic metabo-
dipine into the urine (hr-1 ) lite in the body at infinite time. (mg)
5) kf = rate constant of excretion of Nife- 22) Vm1 = Volume of distribution of the
dipine into feces (hr-1 ) acidic metabolite in the body (L)
6) km1 = rate of metabolism of Nife- 23) Cm1 = Concentration of acidic metab-
dipine in the body (hr-1 ) olite in the body at time = 0 (mic/L)
7) K1 = elimination rate constant of Nifedipine in Im1 = Intercept of the acidic metabolite con-
the body; the summation of all of the ways that it is centration vs time profile = 181.2 mic/L
removed from the body. (hr-1 )
24) AUCmet = Area Under the Curve of
8) T1/2 of Nifedipine in the body (hr) the metabolite plasma concentration vs
time profile (mic/L*hr)
9) X0 = Mass of Nifedipine in the body
at time 0 (mg) AUMCmet = Area Under the First Moment
Curve of the metabolite plasma concentration vs
10) Xinf = Mass of Nifedipine in the body time profile = 35700 mic/L*hr2
at time infinite time (mg)
25) Xm1u0 = Mass of acidic metabolite
11) Xuinf = Mass of unchanged Nife- in urine at time = 0 (mg)
dipine in the urine at infinite time (mg)
26) Xm1uinf = Mass of acidic metabolite
12) Xfinf = Mass of unchanged Nife- in urine at time = infinity (mg)
dipine in the feces at infinite time (mg)
27) Xm1f0 = Mass of acidic metabolite in
13) V = Volume of distribution of Nife- feces at time = 0 (mg)
dipine (L)
28) Xm1finf = Mass of acidic metabolite
14) Cp0 = Concentration of Nifedipine in in feces at time = infinity (mg)
the body at time 0. (mic/L)
29) Km1u = Rate constant of excretion of
15) AUCiv = Area under the plasma con- acidic metabolite into urine (hr-1 )
centration of Nifedipine vs time curve of
the IV dose (mic/L*hr) 30) Km1f = Rate constant of excretion of
acidic metabolite into feces (hr-1 )
16) First trapazoid of the AUCiv (mic/
L*hr) 31) Km2=Rate constant of formation of
lactone metabolite in body =rate of metabolism of
17) Last trapazoid of the AUCiv (mic/ the acidic metabolite in the body (hr-1 )
L*hr) 32) K2 = Km1f + Km1u + Km2 = sumation of
all of the ways that the acidic metabolite is eliminated from the
body (hr-1 )

33) Xm20 = Mass of lactone metabolite 38) Xm2finf = Mass of lactone metabolite
in body at time = 0 (mg) in feces at time = infinity (mg)
34) Xm2inf = Mass of lactone metabolite K3 = Km2f + Km2u = the sumation of all of
in body at time = infinity (mg) the ways that the lactone can be eliminated =
0.138 hr.-1
35) Cm2inf = Concentration of lactone
metabolite in the body at time = infinity (0) 39) Km2u = Rate constant of excretion of
lactone metabolite into urine (hr -1 )
36) Xm2u0 = Mass of lactone metabolite
in urine at time = 0 (mg) 40) Km2f = Rate constant of excretion of
lactone metabolite into feces (hr -1 ) .
37) Xm2uinf = Mass of lactone metabo-
lite in urine at time = infinity (mg)
PROBLEM TABLE 11 - 1. Answer Pool Any number from the answer pool may be used
once, more than once, or not at all
Negative Numbers Small Numbers Big Numbers

A -0.0001 0 13
B -0.0010 0.010 15.1
C -0.0100 0.018 17
D -0.0180 0.028 20
E -0.0280 0.042 25
F -0.0375 0.070 38.9
G -0.0750 0.085 50
H -0.0850 0.110 85
I -0.110 0.138 170
J -0.138 0.375 181.2
A -0.375 0.750 295
B -0.750 1.30 415
C -1.30 1.85 434
D -1.85 2.0 787
E -2.0 2.67 2100
F -2.67 3.6 3570
G -3.6 5.0 8500
H -5.0 7.5 21000
I -7.5 8.5 35700
J -10 9.9 85000

14.1.3 NIFEDIPINE SOLUTIONS

X
km1
km2
Graph #1 Graph #2
- 0.75 mmHg/hr
Nifedipine R vs T
14 14
13
13
12
RESPONSE (MMHG)
12
11
11
10
Response (mmHg)
9
10
8
9 7
2 mm Hg
6
8
0 2 4 6 8 10
101 102 103
Time (hr)
/mL)
L)
Graph #3 Nifedipine IV Bolus Graph #4

Nifedipine IV bolus - Metabolite
103
103
181.2 mic/L = Intercept (given)
CONCENTRATION MIC/L
CONCENTRATION MIC/L
100
102
102
50 1.85 hr
10 hrs
101
2 3 4 5 6 7 8 101
0 4 8 12 16 20 24
Time (hours)
Time (hours)

dR
1. ------- = – 0.75mmHg ⁄ hr Slope from graph # 2
dT
dR
2. ------------ = 2.0mmHg Slope from graph # 1
d ln C
dR
-------
3. d------------ dT - = –-------------
ln C = ------------ 0.75 = – 0.375hr –1 Answer #1-
-------------------------
dT dR
------------ 2 Answer #2
d ln C
4. kr = 0, Nifedipine is not excreted into the urine, it is metabolized entirely K1 = k m1 from pkin description
5. kf = 0, Nifedipine is not found in the feces, only the metabolites are. K1 = k m1 from pkin description
0.693 –1
6. km1, Rate of metabolism of Nifedipine in the body = ---------------- = 0.375 hr from graph #3
1.85hr
–1
7. K1, Elimination rate constant of Nifedipine in the body = 0.375hr from graph #3
8. T 1 ⁄ 2 = 1.85 hr from graph #3
9. Xo = ( 3.6 + 15.1 + 1.3 + 5.1 ) = 25mg from pkin description = Σ ( X mu1 + X mu2 + X mf 1 + X mf2 )
10. Xinf = 0 from pkin description
11. X u ( inf ) = 0 from pkin description
12. X f ( inf ) = 0 from pkin description
Dose- = -------------------------
25mg - • 1000mic
13. V = ------------ --------------------- = 85L
Cp o 295mic ⁄ L 1mg
14. 295mic ⁄ L Cp0 extrapolated back to t = 0 obtained from graph #3

Cp 295 = 787mic ⁄ L ⋅ hr
15. AUC iv = ---------o = ------------- as an estimate. Using Trapazoidal rule:
k 0.375
 Cp o + Cp 1 Cp 1 + Cp 2 Cp 2 + Cp 3 Cp 3 + Cp last Cp last 
Σ  -------------------------
- ⋅ ∆t 1 + -------------------------
- ⋅ ∆t2 + -------------------------
- ⋅ ∆t 3 + ------------------------------- ⋅ ∆t last + --------------- 
 2 2 2 2 K1 
 14.6 mcg
Σ  295 + 139- ⋅ 2 + 139
----------------------- + 65.6 ⋅ 2 + 65.6
------------------------- + 31.1- ⋅ 2 + 31.1
-------------------------- + 14.6- ⋅ 2 + -------------
-------------------------- ----------hr
 2 2 2 2 0.375  L
Σ { 434 + 204.6 + 96.7 + 45.7 + 38.9 } mcg

----------hr = 821.9mcg
----------hr
L L

16
Cp o + Cp 1
-------------------------- ⋅ ∆t =  (----------------------------
295 + 139 )- ⋅ 2 = 434mic ⁄ L ⋅ hr
2  2 
Cp L 14.6
17. ---------- = ------------- = 38.9mic ⁄ L ⋅ hr
k 0.375
2
18 AUMC = AUC ⋅ MRT = 787 ⋅ 2.67 = 2100mic ⁄ L ⋅ hr estimate. Using the trapazoidal rule:
 T 0 ⋅ C p o + T1 ⋅ C p1 T1 ⋅ C p1 + T 2 ⋅ C p 2 T2 ⋅ C p2 + T3 ⋅ C p3 T 3 ⋅ C p 3 + T last ⋅ C p last T last ⋅ C p last Cp last 

Σ  ----------------------------------------------
- ⋅ ∆t 1 + ----------------------------------------------
- ⋅ ∆t 2 + ----------------------------------------------
- ⋅ ∆t 3 + ---------------------------------------------------------
- ⋅ ∆t last + ------------------------------
- + ---------------
2
 2 2 2 2 K1 K1 
 0 ⋅ 295 + 2 ⋅ 139 2 ⋅ 139 + 4 ⋅ 65.6 4 ⋅ 65.6 + 6 ⋅ 31.1 6 ⋅ 31.1 + 8 ⋅ 14.6 8 ⋅ 14.6 14.6  mcg 2
Σ  --------------------------------------- ⋅ 2 + ---------------------------------------- ⋅ 2 + ------------------------------------------ ⋅ 2 + ------------------------------------------ ⋅ 2 + ------------------ + ----------------  ----------hr
 2 2 2 2 0.375 0.375  L
2
mcg 2
Σ { 278 + 540.4 + 449 + 303.4 + 311.47 + 103.82 } = 1986.1----------hr
L
1
19. MRT iv = --- = 2.67hr estimate. Using trapazoidal rule and definitions
k
mcg 2 mcg 2
AUMC trap 1986.1----------hr AUMC est 2100 ----------hr
L L
MRT IV = --------------------------- = ------------------------------------ = 2.42 hr ≅ ------------------------ = ------------------------------- = 2.67 hr
AUC trap mcg AUC est mcg
821.9----------hr 787 ----------hr
L L
20. X m1 ( o ) = 0 from pkin description
21. X m1 ( inf ) = 0 from pkin description
22. Vm1 = 170L

k m1 ⋅ X 0 –K2t – K1t
From LaPlace transforms, the equation for the metabolite is - {e
Cp m = --------------------------------------- –e }
( K1 – K2 ) ⋅ V dm
m1 0 k ⋅X
the intercept, I, given as 181.2 mic/L in the data = ---------------------------------------
- .
( K1 – K2 ) ⋅ V dm
k m1 ⋅ X 0 0.375 ⋅ 25mg
Thus V dm = ----------------------------------------------------- = ---------------------------------------------------------------- = 169.6 L
mic mg
( K1 – K2 ) ⋅ 181.2--------- ( 0.375 – 0.07 ) ⋅ 0.1812-------
L L
23. C m1 ( 0 ) = 0 from pkin description

24. AUC met = 2100mic ⁄ L ⋅ hr
PROBLEM TABLE 11 - 1. Nifedipine Data
Cpm ( n ) + Cpm ( n + 1 ) t
-------------------------------------------------------- t AUC
Time (hr) Cpm (mcg/L) 2 ∆T ( n ) AUC trap 0
0 0
0.5 24.7 0 + 24.7 0.5 6.175 6.175
-------------------
2
1 44.4 24.7 + 44.4 0.5 17.275 23.45
---------------------------
2
2 71.8 44.4 + 71.8 1 58.1 81.55
---------------------------
2
4 96.5 71.8 + 96.5 2 168.3 249.85
---------------------------
2
6 100 96.5 + 100 2 196.5 446.35
-------------------------
2
8 94.7 100 + 94.7 2 194.7 641.05
-------------------------
2
12 76.5 94.7 + 76.5 4 342.4 983.45
---------------------------
2
24 34 76.5 + 34 12 663 1646.45
----------------------
2
∞ 0 Cpm last 485.7 2132.15
+ -------------------
-
K small
25. X m1u ( 0 ) = 0 from pkin description
26. X m1u ( inf ) = 15.1mg given in data
27. X m1f ( 0 ) = 0 from pkin description
28. X m1f ( inf ) = 3.6mg given in data
k m1u Xm1u k m1u

= 15.1mg
–1 –1
29. k m1u = 0.042hr ----------- = ------------ = -------------------- ------------------ thus k m1u = 0.042hr
K2 Xo – 1 25mg
0.07hr
k m1f X m1f k m1f
= 3.6mg
–1 –1
30. k m1f = 0.01hr ---------- = ----------- = -------------------- --------------- thus k m1f = 0.01hr
K2 Xo –1 25mg
0.07hr
–1 –1 –1 –1
31. k m2 = 0.018hr 0.07 hr = K 2= k m1f + k m1u + k m2 = 0.01 hr + 0.042 hr + k m2

–1
32. K2 = 0.07hr From your LaPlace Transforms, you know that the equation is bi-exponential, with one of
the slopes being K1 and the other being K2. The terminal slope of graph #4 is 0.07 hr -1, which is not K1 (0.375 hr -1).
So it must be K2.
33. X m2 ( 0 ) = 0 from pkin description
34. X m2 ( inf ) = 0 from pkin description
35. C m2 ( inf ) = 0 from pkin description
36. X m2u ( 0 ) = 0 from pkin description
37. X m2u ( inf ) = 5.0mg given in data
38. X m2f ( inf ) = 1.3mg given in data
–1 k m2u k m2u X m2u 5.0mg

39. k m2u = 0.11hr ----------------------- = ----------
- = ----------------------------- = ------------------------------------
-
–1 K3 X m2u + Xm2f 5.0mg + 1.3mg
0.138hr
–1 k m2f k m2f Xm2f 1.3mg -

40. k m2f = 0.028hr ----------------------- = ---------
- = ----------------------------- = ------------------------------------
–1 K3 X + X 5.0mg + 1.3mg
0.138hr m2u m2f

Practice Exams: Section 1 : Enalapril - Section 1
14.2 Enalapril - Section 1

Citation
14.2.1 ENALAPRIL DATA

Enalapril (Vasotec ®) is an angiotensin converting enzyme (ACE) Inhibitor effective in the treatment of hypertension
and chronic heart failure (CHF). The parent compound is weakly active, while its sole metabolite, Enalaprilat, exhib-
its almost all of the pharmacological activity. Original work on the pharmacokinetics of Enalapril showed the parent
drug, Enalapril and its metabolite, Enalaprilat, show up in both feces and urine.
The following data was offered regarding the Pharmacological response of Enalaprilat as judged by the fall in Seated
Systolic Blood Pressure (SSBP).
PROBLEM TABLE 11 - 1. Enalapril - Section 1: Pharmacological Profile
Fall in SSBP Time (hr) after Fall in SSBP

(mmHg) Max Dose (mg) (mmHg)
15 3 1 0
12 7 5 1
10 10 10 5
8.6 12 15 10
6 18 20 16
4 24 25 20
30 24
PROBLEM TABLE 11 - 1. Enalapril - Section 1 IV Bolus Profile from a 5 mg dose
Cumulative Cumulative Cumulative

Cumulative Enalapril Enalaprilat Enalaprilat
Time Cp Cpm Enalapril in in feces in urine in feces
(hr) (ng/mL) (ng/ml) urine (mg) (mg) (mg) (mg)
1 29 7.5 0.41 0.12
2 17 11.6 0.65 0.20
3 10 13.8 0.80 0.24
4 5.9 14.9 0.88 0.26
6 2 15.2 0.96 0.30
8 14.7
10 13.8
20 9.8
30 6.9
40 4.9
50 3.4 1.0 0.3 2.25 1.45

The intercept of Cp m vs t was found to be 19.8 ng ⁄ mL and a total of 2.25 mg of enalaprilat was found in the
urine while 1.45 mg was found in the feces.
PROBLEM TABLE 11 - 1. Enalapril Answer Pool
Negative Small Small Medium Large

Numbers Numbers Numbers Numbers Numbers
A 0.000 0.014 1.00 14.5 100
B -0.014 0.021 1.45 19.8 174
C -0.021 0.030 .1.90 30.3 528
D -0.030 0.035 2.25 33.0 395
E -0.035 0.039 3.75 37.5 693
F -0.110 0.110 5.00 39.5 834
G -0.390 0.150 6.93 50.0 1740
H -0.530 0.300 8.00 70.0 5280
I -0.700 0.390 9.00 94.0 14400
J -0.900 0.530 9.76 97.0 16000
Equation Answer Pool:
k mu k m Xo 1 – e – K2t 1 – e – K1t ( k mf k m Xo ) 1 – e –K2t 1 – e – K1t

A ------------------------
- --------------------- – --------------------- B ------------------------
- --------------------- – ---------------------
( K1 – K2 ) K2 K2 ( K1 – K2 ) K2 K1
km ⋅ X 0 k mu k m Xo
C ---------------------------------------- ⋅ – K2t K1t D. ------------------------- ⋅ – K2t K1t
( K1 – K2 ) ⋅ Vd m ( e ) – (e ) ( K1 – K2 ) ( e ) – (e )
km ⋅ X 0 X 0 – K1t
E ------------------------- ⋅ – K2t K1t F ------ e
( K1 – K2 ) ( e ) – (e ) V
– K1t k – K1t
G kr ⋅ X 0 e H ------f- ⋅ X0 ( 1 – e )
K1
k – K1t – K1t
I ------u- ⋅ X0 ( 1 – e ) J X0e
K1

14.2.2 ENALAPRIL QUESTIONS

Find the equation for: 18) kmf, the fecal excretion rate constant
for metabolite, Enalaprilat, in plasma.
1) X, the mass of parent drug, Enalapril, in
the body. 19) K1, the elimination rate constant of
parent drug in plasma(the summation of all
2) Xu, the mass of parent drug, Enalapril,
processes which remove Enalapril)
in urine.
20) K2, the elimination rate constant of
3) dX u/dt, the rate of excretion of parent metabolite in plasma(the summation of all
drug, Enalapril, in urine. processes which remove Enalaprilat).
4) Xf, the mass of parent drug, Enalapril, in
feces.
Find the intercept of the graph of:
5) Xm, the mass of metabolite, Enalaprilat,
21) Cp vs T
in the body.
22) Cpm vs T (terminal extrapolated line)
6) Xmu, the mass of metabolite, Enalapri-
lat, in urine. 23) dXu/dt vs T
7) dXmu/dt, the rate of excretion of metab- 24) dXf/dt vs T
olite, Enalaprilat, in urine.
8) Xmf, the mass of metabolite, Enalapri-
Find the slope of the terminal portion of
lat, in feces.
the graph of:
9) Cp, the plasma concentration of parent
25) Cp vs T
drug, Enalapril.
26) Cpm vs T
10) Cpm, the plasma concentration of
metabolite, Enalaprilat. 27) dXu/dt vs T
28) dXf/dt vs T
Find the value of:
11) dR/dT Find the area under the curve of the
12) dR/d(ln(C)) graph of
13) d(ln(C))/dT 29) Cp vs T(first trapazoid only)
14) kr, the renal excretion rate constant of 30) Cpm vs T(first trapazoid only)
parent drug, Enalapril, in plasma.
31) Cp vs T(from Tlast to T ∞ only)
15) kf, the fecal excretion rate constant of
parent drug, Enalapril, in plasma. 32) Cpm vs T(from Tlast to T ∞ only)
16) km, the metabolism rate constant
ofparent drug, Enalapril, in plasma. 33) Cp vs T
17) kmu, the renal excretion rate constant 34) Cpm vs T

for metabolite, Enalaprilat, in plasma. 35) dXu/dt vs T

36) dXmu/dt vs T 49) XMU0

37) T*Cp vs T 50) XMF0
38) T*Cpm vs T 51) X ∞
Find the value of :
52) X u ∞
39) AUC(enalapril)
40) AUMC(enalapril) 53) X f ∞
41) MRT(enalapril) 54) X m∞

42) AUC(enalaprilat) ∞
55) X mu
43) AUMC(enalaprilat)
∞
56) X mf
44) MRT(enalaprilat)
57) Cp0
45) X0
58) Cpm0
46) XU0
59) Vd
47) XF0
60) Vdm
48) XM0
14.2.3 ENALAPRIL SOLUTIONS

Enalapril Model
kf kr
Xf X Xu
km
kmf kmu
Xmf Xm Xmu

sponse
esponse
R vs C RESPONSE DATA
R vs T
24
15
22
14
20
13
18
12
16
14
11
12 10
10 9
8
10 10
2 4 6 8 10 12
Concentration
Time (hr)
Enalapril Enalapril IV Bolus - Metabolite
102
102
101
101
100
0 1 2 3 4 5 6
100
Time (hrs) 0 10 20 30 40 50
Time (hours)

– k1t
1 X = Xoe
k – k1t
2 X u = ----r- X o ( 1 – e )
k1
– k1t
3 dx u ⁄ dt = k r Xo e
k – k1t
4 X f = -----f Xo ( 1 – e )
k1
km X o – k2t – k1t
5 -(e
Xm = -------------------- –e )
( k1 – k2 )
k mu k m Xo 1 – e –k2t 1 – e –k1t
6 Xmu = --------------------- -------------------- – --------------------
( k1 – k2 ) k2 k1
dX mu k mu k m Xo – k2t – k1t
7 ------------- = --------------------- ( e –e )
dt k1 – k2
( k mf k m Xo ) 1 – e – K2t 1 – e –K1t
8 X mf = ------------------------
- --------------------- – ---------------------
K1 – K2 K2 K1
– k1t D- e – k1t
9 C p = C po e = ------
Vd
km ⋅ X 0
10 -⋅
Cp m = --------------------------------------- – K2t K1t
( K1 – K2 ) ⋅ Vd m ( e ) – (e )
11 dR ⁄ dt = – 0.7
12 dR ⁄ d ( ln c ) = 20
13  d ( ln c ) ⁄ dt = –----------
0.7 = – 0.035
 20 
∞
Xu
- • k 1 = 1--- • 53 = 0.106 = 0.11hr
–1
14 k r = ------
Xo 5
∞
Xf
- • k 1 = 0.3
–1
15 k f = ------ ------- • 0.53 = 0.0318 = 0.03 hr
Xo 5

∞ ∞
Xmu + X mf
• k 1 = 2.25 + 1.45- • 0.53 = 0.39 hr – 1
16 k m = ------------------------ --------------------------
Xo 5
∞
Xmu
• k 2 = 2.25
–1
17 k mu = ------------------------ ---------- • 0.035 = 0.21hr
∞ ∞ 3.7
Xmu + Xmf
∞
Xmf
• k 2 = 1.45
–1 –1
18 k mf = ------------------------ ---------- ⋅ 0.035hr = 0.014 hr
∞ 3.7
Xmu + Xmf
–1
19 K1 = 0.53hr = slope of Cp vs T = k m + kf
–1
20 K2 = 0.035hr = terminal slope of graph Cp m vs T = k mu + k mf
21 Cp ( 0 ) = 50ng ⁄ mL
22 I = 19.8 ng ⁄ mL
dX
23 --------u- vs T I = 0.53
dt
24 k f ⋅ X0 = ( 0.03 ⋅ 5 ) = 0.15ng ⁄ mL
PROBLEM TABLE 11 - 1. Urinary Rate Set up
∆Xu ∆X u
∆X u ---------- ----------
T mid Time ∆T Xu ∆T ∆T
0 0
0.5 1 1 0.41 0.41 0.41 ⁄ 1 0.41
1.5 2 1 0.65 0.24 0.24 ⁄ 1 0.24
2.5 3 1 0.80 0.15 0.15 ⁄ 1 0.15
3.5 4 1 0.88 0.08 0.08 ⁄ 1 0.08
5 6 2 0.96 0.08 0.08 ⁄ 2 0.04
–1
25 0.53 hr
–1
26 0.035 hr

–1 16000
27 0.53 hr 44 --------------- = 30.3hr
528
–1
28 0.53 hr
45 X 0 = 5mg
29
( 50 + 29 )- ⋅ 1 = 39.5ng ⁄ mL ⋅ hr 46 Xu ( 0) = 0
----------------------
2
47 Xf ( 0 ) = 0
30
( 0 + 7.5 ) ⋅ 1 = 3.75ng ⁄ mL ⋅ hr 48 Xm ( 0 ) = 0
---------------------
2
49 Xmu ( 0 ) = 0
2
31 ---------- = 3.77ng ⁄ mL ⋅ hr 50 Xmf ( 0 ) = 0
0.53
3.4 - = 97ng ⁄ mL ⋅ hr ∞
32 ------------ 51 X = 0
0.035
∞
52 Xu = 1mg
33 94 ng ⁄ mL ⋅ hr
34 53
∞
Xf = 0.3mg = ( 5 – 1 – 2.25 – 1.45 )
19.8  ------------ 1 - = 528ng ⁄ mL ⋅ hr
1 - – ---------
0.035 0.53
∞
54 Xm = 0
dX
35 AUC  --------u- vsT = 1mg ∞
 dt  55 X mu = 2.25mg
dX mu ∞
36 AUC  ------------
- vsT = 2.25mg 56 X mf = 1.45mg
 dt 
57 Cp 0 = 50ng ⁄ mL
2
37 174 ng ⁄ mL ⋅ hr
58 Cp m ( 0 ) = 19.8ng ⁄ mL
2
38 16000 ng ⁄ mL ⋅ hr
dose- = 100L
39 94 ng ⁄ mL ⋅ hr Vd = ------------
Cp ( 0 )
59
2
40 174 ng ⁄ mL ⋅ hr 60
41 1.9 hr ( km ⋅ X0 ) ( 0.39 ⋅ 5 )
Vd m = --------------------------- = -----------------------------------------------------
( K1 – K2 )I ( K1 – K2 ) ( 0.0198
42 528 ng ⁄ mL ⋅ hr
2
43 16000 ng ⁄ mL ⋅ hr

Practice Exams: Section 1 : Ciprofloxacin Section 1
14.3 Ciprofloxacin Section 1
14.3.1 CIPROFLOXACIN DATA

Ciprofloxacin (Cipro ®) is a fluoroquinolone, synthetic broad spectrum antibacterial agent. It is reasonably well
absorbed orally and is excreted into the urine and is metabolized to four known metabolites which are also excreted
into the urine. Before an accurate analytical assay was worked out for ciprofloxacin, a microbiological assay was used
to determine the pharmacokinetics. This assay utilized the ability of ciprofloxacin to kill microorganisms grown on an
agar plate and create a clear zone of no growth, the zone of inhibition. The following data was collected from that pro-
cedure: (Intercept for the extrapolated metabolite graph was 0.372 mg/L)
Data Set 0ne Data Set Two
Pharmacological Response Pharmacological Response

Zone -mm Time (hrs) zone - mm Concentration Spiked plasma
27 1 4.7 0.01
23.2 5 13.5 0.05
20.4 8 17.3 0.1
18.5 10 19.5 0.15
5.2 24 21 0.2
23.5 0.3
28 0.7
PROBLEM TABLE 11 - 1. Data from 500 mg IV Bolus Cipro.
Time Cp Cpm Interval Cipro (mg)

(Hrs) (mg/L) (mg/L) (hours) in urine
0.5 0.045 0-4 184
1 3 0.077 4-8 92
2 2.53 0.115 8 - 12 46
3 2.12 0.129
4 1.79 0.128
5 0.119
6 1.26 0.108
8 0.893 0.084
10 0.062
12 0.045
16 0.023
18 0.016
20 0.012

14.3.2 CIPROFLOXACIN QUESTIONS

From the above information find the pharmacokinetic parameters:
1) K (elimination rate constant of Cipro) (hr-1 )
2) kr (urinary excretion rate constant of Cipro)(hr-1 )
3) km (metabolism rate constant of Cipro)(hr-1 )
4) kmu (urinary excretion rate constant of the metabolites)(hr-1 )
5) Cp0 (IV bolus Cipro) (mic/mL)
6) Vd (Cipro)(L.)
7) Vdm (metabolites)(L.)
8) AUC (Cp vs t for Cipro by IV bolus) (mic/mL * hr)
9) AUMC (t*Cp vs t for Cipro by IV bolus (mic/mL * hr2)
10) MRT (Cipro)(hr)
11) AUC (dXu/dt vs t(mid) for Cipro by IV bolus) (mg)
12) Xinf (Cipro in the body at infinite time)
13) Xuinf (Cipro in the urine at infinite time)
14) Xminf (metabolites in the body at infinite time)
15) Xmu inf (metabolites in the urine at infinite time)
16) T1/2 (Cipro)(hr)
17) Clearance (Cipro)(L/hr)

18) dR/dT (mm/hr)
19) dR/d(lnC) (mm)
20) d(lnC)/dt (Cipro)(hr-1)
21 Slope of Cp vs T ([Cipro] vs t) on semi-log paper
22 Slope of dXu/dt vs T(mid) vs t on semi-Log paper
23 Slope of terminal portion of Cpm vs T on semi-log paper
24) Slope of stripped portion of Cpm vs T on semi-log paper
25) Equation for the rate of formation of the metabolites in the urine (dXmu /dT vs T)
a) kmu * Xo * (e-Kt - e-kmut ) / (kmu - K)
b) kmu * km * Xo * (e-Kt - e-kmut ) / (K - kmu)
c) km * Xo * (e-Kt - e-kmut ) / (kmu - K)
d) kmu * km * Xo * {(1-e-Kt )/K- (1-e-kmut )/kmu} / (kmu - K)
e) kmu * km * Xo * (e-Kt - e-kmut ) / (kmu - K)

14.3.3 CIPROFLOXACIN SOLUTIONS

Ciprofloxacin Model
X ku Xu
km
Xm kmu Xmu
Ciprofloxacin
30 Ciprofloxacin
30
25
25
20 20
Response (zone - mm)
15 15
Response (zone - mm)

10
10 5
5 0
0 10 -2 10 -1 10 0
0 5 10 15 20 25
Concentration (mic/mL)
Time (hr)
Ciprofloxacin Ciprofloxacin Metabolite data Ciprofloxacin Urine data

101 100 102
100 10-1
10 -1 10-2
dXu/dt (mg)
101
0 5 10 15 20
0 2 4 6 8
0 2 4 6 8 10
Concentration (mic.mL)
Time (hours) Time (hours)

Tmid (hours)

–1 ∞
1. K = 0.173hr 15 X mu = 125mg
2.
16 T 1 ⁄ 2 = 4.0hr
R ⁄ hr- = 0.13hr – 1
k r = -----0- = 65.13mg
------------------------------
X0 500mg 17 Cl = 24.2L ⁄ hr
dR
3 k m = 0.043hr
–1 18 ------- = – 0.95mm ⁄ hr
dT
–1
4 k mu = 0.462hr dR = 5.5mm
19 -----------------
d ( ln C )
5 Cp 0 = 3.57mic ⁄ mL
20
( ln C ) = – 0.173hr –1
d-----------------
6 Vd = 140L dt
7 Vd m = 200L 21 Slope of Cp vs T = – 0.173
22 Slope of
8 AUC = 20.7mic ⁄ mL ⋅ hr
dX u
Cp vs T --------- vs ( t mid ) = – 0.173
dt
9.
2 23 Slope of terminal portion of
AUMC = 119.7mic ⁄ mL ⋅ hr
Cp m vsT = – 0.173
10 MRT = 5.8hr
24 Slope of stripped portion of
dX u Cp m vsT = – 0.462
11 AUC = 375mg ---------vs ( t mid )
dt
25
12
∞
X = 0 k mu ⋅ k m ⋅ X 0 – Kt – kmut
----------------------------- • (e – e )
( k mu – K )
∞
13 X u = 375mg
∞
14 Xm = 0

Practice Exams: Section 1 : Methylphenidate Section 1
14.4 Methylphenidate Section 1

Citation
14.4.1 METHYLPHENIDATE DATA

Methylphenidate (MP) (Ritalin®) is an effective stimulant in the treatment of narcolepsy in adults and attention deficit
syndrome in children. It is entirely metabolized to the inactive metabolite, Ritalinic Acid (RA), by the liver which is
subsequently excreted unchanged into the urine. Pharmacological response was measured objectively using sleep
latency as measured by encephalography. Sleep latency is the time required to fall asleep in a darkened quiet room.
Pharmacological Response Data
Time (hr) Response (min) Cp (mcg/mL) Response (min)

0.5 22 6 22.5
1 16 5 18
1.5 10 4 15
2 5 3 10
PROBLEM TABLE 11 - 1. Plasma Profiles

(Intercept of extrapolated RA line 0.21
mic/mL)
Plasma Vs. Time Profile

10 mg MP given by IV Bolus
Cp (MP) Cpm (RA)

Time (hr) (mcg/mL) (mcg/mL
0.5 0.091 0.022
1 0.067 0.029
1.5 0.049 0.030
2 0.035 0.028
2.5 0.026 0.024
3 0.019 0.020
4 0.010 0.012
6 0.003 0.004
8 ------- 0.0013

14.4.2 METHYLPHENIDATE QUESTIONS:

From the above information find the phar- 25) d(lnCp)/dt (MP)(hr-1)
macokinetic parameters:
26) The slope of Cp vs T ([MP] vs t) on
1) K (elimination rate constant of MP) (hr -1
semi-log paper
)
27) The equation for Cp vs T ([MP] vs t)
2) kr (urinary excretion rate constant of on semi- log paper
MP)(hr-1 )
28) The slope of terminal portion of
3) km (metabolism rate constant of dXmu/dt vs T(mid) on semi-Log paper
MP)(hr-1 )
29) The equation for dXmu/dt vs T(mid)
4) kmu (urinary excretion rate constant of on semi- log paper
(RA)(hr-1 )
30) The slope of terminal portion of Cpm vs
5) Cp0 (IV bolus MP) (mic/mL) T ([RA] vs t) on semi-log paper
6) Vd (MP)(L.) 31) The equation for Cpm vs T ([RA] vs t)

on semi- log paper
7) Vdm (RA)(L.)
32) The slope of stripped portion of Cpm vs
8) AUC (Cp vs t for MP by IV bolus) (mic/
T ([RA] vs t) on semi-log paper
mL * hr)
33) The equation for Xm (bar) (Laplace domain
9) AUMC (t*Cp vs t for MP by IV bolus equation for RA in the body)
(mic/mL * hr2)
34) The equation for Xm (RA in the body)
10) MRT (MP)(hr)
11) AUC (dXu/dt vs t(mid) for MP by IV
bolus) (mg)
12) AUC (dXmu vs t(mid) for RA)(mg)
13) X0 (MP in the body at zero time)
14) Xm0 (RA in the body at zero time)
15) Xmu0 (RA in the urine at zero time)
16) X1hr (MP in the body at 1 hr.)
17) Xm1hr (RA in the body at 1 hr)
18) Xinf (MP in the body at infinite time)
19) Xuinf (MP in the urine at infinite time)
20) Xminf (RA in the body at infinite time)
21) T1/2 (MP)(hr)
22) Clearance (MP)(L/hr)

23) dR/dT (min/hr)
24) dR/d(lnCp) (%)

14.4.3 METHYLPHENIDATE SOLUTIONS
km
Xm kmu Xmu
Methyl Phenidate R vs C
24
25
Response
22
20 20
0 1
18
15
16
10
Response (min)
14
12
5
10
0 8
10 10
0.5 1.0 1.5 2.0
Concentration
Time (hr)
Methyl Phenidate IV Bolus MP IV Bolus - Metab

100 100
10-1 10-1
10-2
10-2
0 1 2 3 4
0 2 4 6 8
Time (hours)
Time (hours)

–1 21 T 1 ⁄ 2 = 1.1hr
1 K = 0.63hr
2 kr = 0 22 Cl = 50.4L ⁄ hr
dR
3 k m = 0.63hr
–1 23 ------- = – 11.4min ⁄ hr
dT
–1
4 k mu = 0.90hr dR - = 17.5 min
24 --------------------
d ( ln Cp )
5 Cp 0 = 0.125mic ⁄ mL
25
( ln Cp )- = – 0.63hr –1
d--------------------
6 Vd = 80L (change in answer dT
pool)
–1
26 The slope of Cp vs T – 0.63hr
7 Vd m = 115L (change in answer
27 The equation for Cp vsT
pool)
–k ⋅ t
Cp = Cp 0 ⋅ e
8 AUC = 0.20mic ⁄ mL ⋅ hr
9. 28 The slope of terminal portion of
2 dX mu
AUMC = 0.315mic ⁄ mL ⋅ hr ------------
- vsT mid = – 0.63
dT
10 MRT = 1.57hr
29 The equation for
11 AUC = 0 MP is not excreted in dX mu k mu ⋅ k m ⋅ X0 – K1t
the urine ------------- vsT mid = ----------------------------- (e –e )
dT ( K2 – K1 )
12 AUC = 10mg All of RA is 30 the slope of the terminal portion of
excreted in the urine Cp m vsT ( RA )vsT = –0.94
13 X0 = 10mg
31 The equation for
14 Xm ( o ) = 0 km ⋅ X0 – K1t
Cp m vsT ( RA ) = ------------------------- (e –e )
( K2 – K1 )
15 Xmu ( 0 ) = 0
32 The slope of stripped portion
16 X1hr = 5.3 (change in answer – 0.79
pool) km ⋅ X0
33 Xm = ---------------------------------------------
-
17 Xm1hr = 2.8 (change in answer ( s + K1 ) ⋅ ( s + K2 )
pool) 34 The equation for
∞ km ⋅ X 0 – K1t – K 2t
18 X = 0 Xm = ------------------------- (e –e )
( K2 – K1 )
∞
19 Xu = 0
∞
20 Xm = 0

Practice Exams: Section 1 : Adinazolam - Section 1
14.5 Adinazolam - Section 1

Fleishaker [Pharm Res 8 (2): 162-7(1991),Pharm Res 6 (5): 379-86(1989),Psychopharm 99:34-9(1989),Psychopharm 105:181-
5(1991)];Kroboth [J Clin Pharmacol 31:580-6(1991)]; Wagner [Biopharm Drug Dis 8:405-25(1987)].
14.5.1 ADINAZOLAM DATA

Adinazolam (AD) is a triazolobenzodiazepine prodrug which has been shown to have antidepressant activity through
its metabolite, N-desmethyladinazolam (NDMAD). Both AD and NDMAD are excreted into the urine. The following
data regarding AD and NDMAD was collected from the works cited. AD appears to interfere with mental ability. One
of the tests was the ability to Substitute Digits for Symbols (DSST) and the interference of that process was the
response measured below:
PROBLEM TABLE 11 - 1. Pharmacological Response
% Pharm Response Time (hrs) % Pharm Response NDMADC Conc (ng/,L)

59.7 2 33 200
45.3 4 48 300
29.5 6 59 400
15.5 8 68 500
0 12 74 600
From the above information find the pharmacokinetic parameters:
PROBLEM TABLE 11 - 1. Five mg IV bolus dose of AD yieled: (intercept of extrapolated metabolite line is 150 ng/mL)
Plasma Data Urine Data
Time (mid)
Time Cp (AD) Cpm(NDMAD) AD Ecretion Rate
(hr) (ng/mL) (ng/mL) t (mg/hr)
0.5 47 0.5 0.56
1 40 15.4 1 0.48
2 28 23.5 2 0.34
3 27.3 4 0.18
4 14.7 28 6 0.09
5 27
6 7.5 24.9
8 20
10 15
12 11
15 7.5
18 4.2
20 2.8
22 1.9
24 1.2

14.5.2 ADINAZOLAM QUESTIONS

1) K (elimination rate constant of AD) (hr-1 )
2) kr (urinary excretion rate constant of AD)(hr-1 )
3) km (metabolism rate constant of AD)(hr-1 )
4) kmu (urinary excretion rate constant of NDMAD)(hr -1 )
5) Cp0 (IV bolus AD) (ng/mL)
6) Vd (AD)(L.)
7) Vdm (NDMAD)(L.)
8) AUC (Cp vs t for AD by IV bolus) (ng/mL * hr)
9) AUMC (t*Cp vs t for AD by IV bolus (ng/mL * hr2)
10) MRT (AD)(hr)
11) AUC (dXu/dt vs t(mid) for AD by IV bolus) (mg)
12) Xinf (AD in the body at infinite time)
13) Xuinf (AD in the urine at infinite time)
14) Xminf (NDMAD in the body at infinite time)
15) Xmu inf (NDMAD in the urine at infinite time)
16) T1/2 (AD)(hr)
17) Clearance (AD)(L/hr)

18) dR/dT (%/hr)
19) dR/d(lnC) (%)
20) d(lnC)/dt (NDMAD)(hr-1)
21 Slope of Cp vs T ([AD] vs t) on semi-log paper
22 Slope of dXu/dt vs T(mid) vs t on semi-Log paper
23 Slope of terminal portion of Cpm vs T ([NDMAD] vs t) on semi-log paper
24) Slope of stripped portion of Cpm vs T ([NDMAD] vs t) on semi-log paper
25) Xm (bar) (Laplace domain equation for NDMAD in the body)

PROBLEM TABLE 11 - 1. Answer Pool
Numbers LaPlace Forms

a -1.33 -0.1 0 1 10 100 Xo/(s+K)
b -1.55 -0.133 0.1 1.33 12.5 120 Xo/(s+km)
c -2 -0.15 0.133 1.5 20 167 Xo/(s+kmu)
d -3.33 -0.2 0.15 2 30 200 km * Xo / ((s+km) * (s+kmu))
e -4 -0.333 0.2 3 37.5 375 kmu * Xo / ((s+km) * (s+kmu))
f -5 -0.5 0.333 4 40 425 km * Xo / ((s+km) * (s+K ))
g -6.93 -0.693 0.5 5 50 500 kmu * Xo / ((s+K ) * (s+kmu))
h -7.5 -0.73 0.693 6 55.6 630 km * Xo / ((s+K ) * (s+kmu))
i -8.25 -0.85 0.75 6.67 66.7 775 kmu*km*Xo / ((s+K ) * (s+kmu))
j -9 -0.95 0.84 7.5 75 930 kr*Xo / ((s+K ) * (s+kmu))

14.5.3 ADINAZOLAM SOLUTIONS
X ku Xu
km
Xm kmu Xmu
onse %
R vs T
60
Adinazolam metabolite
80
50
70
40
60
Response (%P-col)
30
50
40
20
30
10 10 2 10 3
2 3 4 5 6 7 8
Time (hr) Concentration (ng.mL)
AD IV Bolus - Metab
Adinazolam IV Bolus 102
10 2
101
10 1
100
10 0
0 5 10 15 20 25
0 1 2 3 4 5 6

–1 22 Slope of
1 K = 0.333hr
dX u
–1 ---------vsT( mid ) = – 0.333
2 k r = 0.133hr dt
–1
23 Slope of the terminal portion of
3 k m = 0.2hr Cp m vsT = – 0.2
–1 24 Slope of the stripped portion = -
4 k mu = 0.2hr
0.333
5 Cp 0 = 55.6ng ⁄ mL
km ⋅ X0
25 X m = ---------------------------------------
-
6. Vd = 90L ( s + K ) ( s + k mu )
7 Vd m = 50L
8 AUC = 167ng ⁄ mL ⋅ hr
2
9 AUMC = 500ng ⁄ mL ⋅ hr
10 MRT = 3.0hr
11 AUC m = 2.0mg
∞
12 X = 0
∞
13 X u = 2.0mg
∞
14 Xm = 0
∞
15 Xmu = 3.0mg
16 T1 ⁄ 2 = 2hr
17 Cl = 30L ⁄ hr
dR
18 ------- = – 7.42 %hr
dT
dR = 37.5
19 ----------------- %
d ( ln C )
( ln C ) = – 0.2hr – 1
d-----------------
20
dt
21 Slope of Cp vs T([AD] vs t) = -
0.333

Practice Exams: Section 1 : Labetalol - Section 1
14.6 Labetalol - Section 1

Saotome, et. al (J. Clin. Pcol 1993,33:979- 988)
14.6.1 LABETALOL DATA

Labetalol is a selective α- blocking and nonselective β-blocking agent used in the treatment of hypertension. It is
excreted unchanged into the urine and extensively metabolized. The metabolites are excreted into the urine and bile.
Labetalol reduces diastolic blood presure.
PROBLEM TABLE 11 - 1. P-col Resp vs Time (hrs) P-col Resp v Labetalol Conc
Pharmacological Response Profiles
Decrease in BP Time Decrease in BP Cp

(mm Hg) (hr) (mm Hg) (ng/mL)
22.2 2 14.5 100
20.3 4 16.5 160
18.5 6 19.5 275
16.6 8 22.5 525
PROBLEM TABLE 11 - 1. Data from a 200 mg IV Bolus dose (Intercept of extrapolated Metabolite data = 22.7 mg/hr)
Time Labetalol Metabolite

(mid) Excretion rate Excretion Rate
Time
(hrs) Cp t (mg/hr) (mg/hr)
0.5 364 0.5 1.82 5.1
1 331 1 1.66 8.2
2 274 1.5 9.8
4 187 2 1.37 10.6
6 128 2.5 10.7
8 88 3 10.5
4 0.94 9.5
6 0.64 7.0
8 4.9
12 2.3
18 0.74
24 0.24

14.6.2 LABETALOL QUESTIONS

From the above information find the phar- 21) Clearance (labetalol)(L/hr)
macokinetic parameters:
22) dR/dT (%/hr)
1) K (elimination rate constant of labe-
23) dR/d(lnC) (%)
talol) (hr-1 )
24) d(lnC)/dt (labetalol)(hr-1)
2) K2 (elimination rate constant of labe-
talol metabolites (hr-1 ) 25 Slope of Cp vs T ([labetalol] vs t) on
semi-log paper
3) kr (urinary excretion rate constant of
labetalol)(hr-1 ) 26 Slope of dXu/dt vs T(mid) vs t on
semi-Log paper
4) km (metabolism rate constant of labe-
talol)(hr-1 ) 27 Slope of terminal portion of Cpm vs T
([Metabolites of labetalol] vs t) on
5) kmu (urinary excretion rate constant of
semi-log paper
Metabolites of labetalol)(hr-1 )
28) Slope of stripped portion of Cpm vs T
6) kmb (biliary excretion rate constant of ([Metabolites of labetalol] vs t) on
Metabolites of labetalol)(hr-1 ) semi-log paper
7) Cp0 (IV bolus labetalol) (ng/mL) 29) Xm (bar) (Laplace domain equation for Metabolites
8) Vd (labetalol)(L.) of labetalol in the body)
9) AUC (Cp vs t for labetalol by IV bolus) 30) dXmu / dT (equation for the rate of
(ng/mL * hr) excretion of metabolites into the urine)
10) AUMC (t*Cp vs t for labetalol by IV 31) Fraction of labetalol excreted

bolus (ng/mL * hr2) unchanged.
11) MRT (labetalol)(hr) 32) Fraction of labetalol eliminated as

metabolites in the urine.
12) AUC (dXu/dt vs t(mid) for labetalol by
IV bolus) (mg) 33) Fraction of labetalol eliminated as
metabolites in the bile.
13) AUC (dXmu/dt vs t(mid) for Metabo-
lites (mg))
14) AUC (dXmb/dt vs t(mid) for Metabo-
lites (mg))
15) Xinf (labetalol in the body at infinite time (mg))
16) Xuinf (labetalol in the urine at infinite time (mg))
17) Xminf (Metabolites of labetalol in the body at infi-

nite time (mg))
18) X muinf (Metabolites of labetalol in the urine at infi-

nite time (mg))
19) X mbinf (Metabolites of labetalol in the bile at infi-

nite time (mg))
20) T1/2 (labetalol)(hr)

14.6.3 LABETALOL SOLUTIONS
X ku Xu
km
Xmf kmf Xm kmu Xmu
Labatalol
Labatalol
23
24
22
21 22
20
20
Response (mmHg)
19
Response (mmHg)
18 18
17
16 16
2 3 4 5 6 7 8 14
10 2 103
Time (hr)
Concentration (ng.mL)
Labatalol Labatalol Metabolite Labatalol

102 10 1
103
101
102 10 0
100
Excretion rate (mg/hr)
101 10-1 10 -1
Excretion Rate (mg/hr)
0 2 4 6 8 0 5 10 15 20 25 0 1 2 3 4 5 6
Time (hours) Time (hours) Tmid (hours)

–1 dR
1 K1 = 0.190hr 23 ----------------- = 4.90 %
d ( ln C )
–1
2. K2 = 0.792hr d ( ln C ) –1
24 ----------------- = – 0.190hr
–1 dt
3 k r = 0.01hr
–1
–1 25 Slope of Cp vs T = – 0.190hr
4 k m = 0.18hr
26 Slope of
–1 dX u
5 k mu = 0.38hr --------- vsT( mid ) vs ( t ) = – 0.190
dt
–1
6 k mb = 0.41hr 27 Slope of terminal portion
of Cp m vsT = – 0.190
7 Cp 0 = 400ng ⁄ mL
28 Slope of stripped portion of
8 Vd = 500L
Cp m vsT = – 0.79
9 AUC = 2105ng ⁄ mL ⋅ hr
km ⋅ X 0
10 29 X m = -----------------------------------------
-
( s + K1 ) ( s + K2 )
2
AUMC = 11072ng ⁄ mL ⋅ hr
30
11 MRT = 5.26hr X mu ( k mu ⋅ k m ⋅ X 0 ) – K2t – K1T
--------- = ---------------------------------- ( e –e )
dt ( K1 – K2 )
12 AUC = 10.5mg
31 Fraction of labetalol excreted
13 AUC = 91.2mg
10.5
unchanged: ---------- × 100 = 5.25 %
14 AUC = 98.3mg 200
∞ 32 Fraction of labetalol excreted as
15 X = 0 metabolites in urine:
∞ 91.2
16 X u = 10.5mg ---------- × 100 = 45.6 %
200
∞ 33 Fraction of labetalol eliminated as
17 Xm = 0
metabolites in bile:
∞ 98.3
18 Xmu = 91.2mg ---------- × 100 = 49.15 %
200
∞
19 Xmb = 98.3mg
20 T1 ⁄ 2 = 3.64hr
21 Cl = 95L
dR
22 ------- = – 0.93 %hr
dT

Practice Exams: Section 1 : Zidovudine Section 1
14.7 Zidovudine Section 1
14.7.1 ZIDOVUDINE DATA

Zidovudine (ZDV - formerly azidithymidine (AZT)) is used to treat HIV positive patients with AIDS and AIDS related
complex (ARC). The in vitro virustatic concentration is 250 mic/mL. While the pharmacokinetics of ZDV is complex,
we can approximate it with the following model. ZDV is excreted unchanged into the urine to UZDV. It is metabo-
lized by hepatic glucuronidation to an inactive metabolite, GZDV, and also metabolized by intracellular phosphoryla-
tion to the active metabolite, ZDV-TP. Both metabolites are excreted into the urine (UGZDV and UZDV-TP). The
anti-retroviral activity was shown in the following data:
PROBLEM TABLE 11 - 1. ZDV-TP Response vs time and response vs concentration data
Pharmacological Response Data
Concentration Activity Time Activity

ZDV-TP (ng/mL) % (min) %
100 80 0 100
90 76.8 30 100
75 68.5 60 100
50 52.3 120 92
25 24.5 240 82
360 72
480 62
PROBLEM TABLE 11 - 1. 100 mg dose ZDV given by IV Bolus to 70 KG patient
Time Cp ZDV Cpm GZDV Interval UZDV Collected Rate of AUC

(hours) (ng/mL) (ng/mL) (hrs) (mg) excretion data UGZDV (mg)
0.25 40 0-1 9.2 60
0.5 75 1-2 4.8
0.75 100 2-3 2.5
1 315 125 4-6 1
1.5 150
2 170 160
3 91 160
4 48 145
6 13 100
8 65
10 40
12 25

Please use the following nomenclature:

D = Dose of ZDV
K = elimination rate constant of ZDV
kr = excretion rate constant of ZDV
kmu1 = excretion rate constant of ZDV-TP
kmu2 = excretion rate constant of GZDV
km1 = metabolism rate constant of ZDV to ZDV-TP
km2 = metabolism rate constant of ZDV to GZDV

14.7.2 ZIDOVUDINE QUESTIONS

1) Using Laplace transforms, find the 14) What is the terminal slope (*-1) of
equation for the rate of excretion of GZDV ln(GZDV) vs t (hr^-1)?
into the urine. (For this question use the
15) What is the terminal slope (*-1) of
following answer set:
ln(dUZDV/dt) vs t (hr^-1)?
a= I only
16) What is the intercept of ZDV vs t (ng/
b= III only mL)?
c = I + II only 17) What is the intercept of dUZDV/dt vs t
(mg/hr)?
d = II + III only
18) What is the intercept of the extrapo-
e = All three
lated line from plasma GZDV vs time data
(ng/mL)?
I (kmu2*km2*D/(K-kmu2))*(exp(-K*t)) 19) What is the intercept of the extrapo-
II (kmu2*km2*D/(K-kmu2))*(exp(- lated line from dUGZDV/dt vs time data
kmu2*t)) (mg/hr)?
III -(kmu2*km2*D/(K-kmu2))*(exp(- 20) What is the Cp0 of ZDV (ng/mL)?

K*t)) 21) What is the volume of distribution of
ZDV (L)?
2) Using linear regression on the pharma- 22) What is the volume of distribution of
cological response / concentration profile, GZDV (L)?
what was the Summation of XY? 23) What is the clearance of ZDV (L/hr)?
3) What is d%R/d(lnC)(%)? 24) What is the half life of ZDV (hr)?
4) What is d%R/dt (%/hr)? 25) What is the MRT of ZDV (hr^-1)?
5) What is K (hr^-1)? 26) What is the AUC of the first trapazoid
6) What is kr (hr^-1)? of ZDV vs time (ng/mL*hr)?
7) What is km1 (hr^-1)? 27) What is the AUC(from 0 to infinity) of

the IV bolus ZDV plasma data (ng/
8) What is km2 (hr^-1)? mL*hr)?
9) What is kmu1 (hr^-1)? 28) How much ZDV is in the body at infi-
10) What is kmu2 (hr^-1)? nite time (mg)?
11) What is the terminal slope (*-1) of 29) How much GZDV is in the body at
ln(ZDV) vs t (hr^-1)? infinite time (mg)?
12) What is the terminal slope (*-1) of 30) How much ZDV-TP is in the body at
ln(ZDV-TP) vs t (hr^-1)? infinite time (mg)?
13) What is the terminal slope (*-1) of 31) How much ZDV is in the urine
ln(ZDV-TP) vs t (hr^-1)? (UZDV) at infinite time (mg)?
32) How much GZDV is in the urine
(UGZDV) at infinite time (mg)?

33) How much ZDV-TP is in the urine

(UZDV-TP) at infinite time (mg)?

14.7.3 ZIDOVULDINE SOLUTIONS
Xm1 km1 X ku Xu
km2
kmu1
Xmu1 Xm2 kmu2 Xmu2
Zidovudine Zidovudine
110 90
100 80
70
90
60
80 50
Response (% Activity)
70 40
Response (% Activity)
30
60 20
0 100 200 300 400 500
10 1 102
Time (min)
Zidovudine Zidovudine Metobolite Zidovudine Urine data

103 103 102
102 102 101
101 101
100
UZVD (mg)
0 1 2 3 4 5 6 0 2 4 6 8 10 12
10-1

0 1 2 3 4 5
Tmid (hours)

1. Answer is D - II and III 26 457.5ng ⁄ mL ⋅ hr

2 1289.2
27 952ng ⁄ mL ⋅ hr
3 40%
28 0
4 -0.08333%hr
29 0
–1
5 K = 0.630hr 30 0
6 k r = 0.125hr
–1 31 20mg
–1
32 60mg
7 k m1 = 0.25hr
33 20mg
–1
8 k m2 = 0.25hr
–1
9 k mu1 = 0.125hr
–1
10 k mu2 = 0.378hr
–1
11 0.630hr
–1
12 0.250hr
13 Skip - same question as #12
–1
14 0.25hr
–1
15 0.630hr
16 600ng ⁄ mL
17 12.6mg ⁄ hr
18 500ng ⁄ mL
19 12.6mg ⁄ hr
20 600ng ⁄ mL
21 166.7L
22 200L
23 105L ⁄ hr
24 1.1hr
25 1.6hr

Practice Exams: Section 1 : Fosinopril Section 1
14.8 Fosinopril Section 1

Kostis et al “Fosinopril: Pharmacokinetics and pharmacodynamics in congestive heart failure” Clin Pcol Ther 58(6) 660-5
(1995); Hui et al “Pharmacokinetics of fosinopril in patients with various degrees of renal function” Clin Pcol Ther 49(4) 457 -66
(1991)
14.8.1 FOSINOPRIL DATA

Fosinopril Sodium is a phosphinic prodrug of the angiotensin converting enzyme (ACE) inhibitor fosinoprilat effective
in the treatment of hypertension and chronic heart failure (CHF). The parent compound is weakly active, if at all. Its
sole metabolite, fosinoprilat, exhibits almost all of the pharmacological activity. After administration, fosinopril is
entirely converted to the active fosinoprolat by esterases in the liver. Unlike other ACE inhibitors, elimination of fos-
inoprilat is divided equally between renal and hepatic pathways (liver metabolism). The following information was
obtained from a 70 Kg male.
Wherever necessary, please use the following symbols:
Cp = plasma concentration of parent drug, fosinopril
Cpm1 = plasma concentration of metabolite, fosinoprilat.
Cpm2= plasma concentration of metabolite of fosinoplilat.
X = amount of parent compound, fosinopril, in the body
Xm1 = amount of metabolite, fosinoprilat, in the body
Xm2 = amount of metabolite of fosinoprilat in the body
Xu = cumulative amount of parent drug in urine.
Xmu1 = cumulative amount of metabolite, fosinoprilat, in urine.
Xmu2 = cumulative amount of metabolite of fosinoprilat in urine.
ku = renal excretion rate constant of parent drug in plasma.
kmu1 = renal excretion rate constant for metabolite, fosinopril, in plasma.
kmu2 = renal excretion rate constant for metabolite of fosinopril in plasma.
kf = fecal excretion rate constant of parent drug in plasma.
kmf1 = fecal excretion rate constant for metabolite, fosinopril, in plasma.
kmf2 = fecal excretion rate constant for metabolite of fosinopril in plasma.
km1 = metabolism rate constant of fosinopril in plasma.
km2 = metabolism rate constant of fosinoprilat in plasma.
K1 = elimination rate constant of parent drug in plasma = summation of all processes which remove fosinopril.
K2 = elimination rate constant of metabolite1 in plasma = summation of all processes which remove fosinoprilat.
K3 = elimination rate constant of metabolite2 in plasma = summation of all processes which remove the metabolite of fosinoprilat.

PROBLEM TABLE 11 - 1. Pharmacological Response data (Six hours after dosing with fosinopril)
Time Fall in SSBP Fall in SSBP Dose

(hr) (mm Hg) (mg Hg) (mg)
3 22 5 10
5 21 11 20
8 19 16 40
11 17 22 80
13 16
Urine Data
Plasma Data (from 20 mg Fosinopril IV bolus)
(from7.5 mg Fosinoprilat IV Bolus) (Intercept 0.855 mg/hr)
Cp
Tme (Fosinoprilat) Interval Amount (Fosinoprilat)
(hours) (ng/mL) (hr) (mg)
1 387 0-1 0.158
2 360 1-2 0.362
3 335 2-3 0.467
4 311 3-4 0.513
6 269 4-6 1.05
6 - 10 1.84
10 - 14 1.42
14 - 22 1.84
22 - 26 0.592

14.8.2 FOSINOPRIL QUESTIONS

From the parent compound, Fosinopril, ♥18) K1, the elimination rate constant of parent drug in
given by IV bolus, find the equation for: plasma , the summation of all processes which remove
Fosinopril.
♣1) X, the mass of parent drug, Fosinopril,
♠19) K2, the elimination rate constant of metabolite in
in the body
plasma , the summation of all processes which remove
♣) Xu, the mass of parent drug, Fosinopril, Fosinoprilat.
in urine.
♣3) dXu/dt, the rate of excretion of parent For fosinoprilat IV, find the value of :
drug, Fosinopril, in urine.
♥20) AUC(fosinoprilat)
♣4) Xf, the mass of parent drug, Fosino-
pril, in feces. ♥21) AUMC(fosinoprilat)
♣5) Xm1, the mass of metabolite, Fosino- ♥22) MRT(fosinoprilat)

prilat, in the body ♥23) Ke for fosinoprilat (hr-1)
♣6) Xm1u, the mass of metabolite, Fosi- ♥24) T 1 ⁄ 2 for Fosinoprilat (hr)
noprilat, in urine.
♣7) dXm1u/dt, the rate of excretion of ♥25) Cp0(fosinoprilat) for iv dose (ng/mL)
metabolite, Fosinoprilat, in urine. ♥26) Vd for Fosinoprilat (L)
♣8) Xm1f, the mass of metabolite, Fosino- ♥27) Cp of Fosinoprilat at eight hours
prilat, in feces. after the IV dose
♣9) Cp, the plasma concentration of parent
drug, Fosinopril
For fosinoprilat given as IV fosinopril,
♣10) Cpm1, the plasma concentration of dXm1/dt, find the value of :
metabolite, Fosinoprilat.
♠28) AUC(fosinoprilat)(mg)
♠29) AUMC(fosinoprilat)
Find the value of:
♠30) MRT(fosinoprilat)
♦11) dR/dT
♠31) K2 for fosinoprilat (hr-1)
♦12) dR/d(ln(Cpm1))
♠32) T ? for Fosinoprilat (hr)
♦13) d(ln(Cpm1))/dT
♠33) K1 for fosinopril (hr-1)
♥14) ku, the renal excretion rate constant of parent drug,
Fosinopril, in plasma.
♥15) km1, the metabolism rate constant of parent drug,

Fosinopril, in plasma.
♠16) kmu1, the renal excretion rate constant for metabo-

lite, Fosinoprilat, in plasma.
♠17) km2, the metabolism rate constant for the metabo-

lite of Fosinoprilat in plasma.

PROBLEM TABLE 11 - 1. Answer Pool
Minus Small Med. Large Equations More equations
A -0.037 0 1.35 155 None ((km1 X0/Vdm )/(K1-K2))(e-K2t-e-K1t )
B -0.050 0.037 5.0 232 X0e-K1t ((km1 X0/Vdm )/(K1-K2))(e-K1t-e-K2t )
C -0.074 0.06 7.4 420 (X0/Vd)e-K1t ((kmu1 X0/Vdm )/(K1-K2))(e-K2t-e-K1t)
D -0.082 0.074 8.2 840 ku X0e -K1t ((kmu1km1 X0)/(K1-K2))(e-K2t-e-K1t )
E -0.10 0.135 9.4 940 kf X0e-K1t ((kmu1km1 X0)/(K1-K2))(e-K1t-e-K2t )
F -0.135 0.5 10 5676 (k u/K1) X0(1-e-K1t) ((kmu1 X0)/(K1-K2))(e-K2t-e-K1t )
G -0.37 0.6 12 13500 (k f/K1) X0(1-e-K1t) ((kmf1km1 X0)/(K1-K2))((1-e-K2t)/K2-(1-e-K1t )/K1)
H -0.50 0.74 13.5 15700 ((km1 X0)/(K1-K2))(e-K2t-e-K1t) ((kmf1km1 X0)/(K1-K2))((1-e-K1t)/K1-(1-e-K2t )/K2)
I -0.6 0.82 15.5 18000 ((km1 X0)/(K1-K2))(e-K1t-e-K2t) ((kmu1km1 X0)/(K1-K2))((1-e-K2t )/K2-(1-e-K1t)/K1)
J -0.74 0.94 18 76700 ((kmu1 X0)/(K1-K2))(e-K2t-e-K1t) ((kmf2km1 X0)/(K1-K2))((1-e-K2t)/K2-(1-e-K1t )/K1)

14.8.3 FOSINOPRIL SOLUTIONS
ku=0
X
K1= km1
km1 K2= kmu1+km2
K3= kmu2
kmu1
Xm1 Xmu1
km2
kmu2
Xm2 Xmu2
R vs Ln(c)
Response
25
R vs T
23
20
22
Response
21
15
20
1 2
19
10
18
5
17
16
0
10 10 15
Concentration 0 2 4 6 8 10 12 14
Time (hr)
Fosinoprilat in Urine
Fosinoprilat 10
0
Excretion Rate (mg/hr)
3
10
Concentration ng/mL
-1
102
10
0 1 2 3 4 5 6 0 5 10 15 20 25
Time (hr) Time (hr)

♣1) X, the mass of parent drug, Fosinopril, in the body B - X0e-K1t

♣) Xu, the mass of parent drug, Fosinopril, in urine. A - none(no drug goes there)
♣3) dXu/dt, the rate of excretion of parent drug, Fosinopril, in urine A = none(no drug goes there)
♣4) Xf, the mass of parent drug, Fosinopril, in feces. A = none(no drug goes there)
♣5) Xm1, the mass of metabolite, Fosinoprilat, in the body H = (km1X0)/(K1-K2)(e-K2t-e-K1t)

♣6) Xm1u, the mass of metabolite, Fosinoprilat, in urine. I =
( k mu1 k m1 X 0 )  1 – e –K2t 1 – e – K1t 
--------------------------------  --------------------- – --------------------- 
( K1 – K2 )  K2 K1 
(k k X )
♣7) dXm1u/dt, the rate of excretion of metabolite, Fosinoprilat, in urine. mu1 m1 0
-{e
D = ------------------------------- –K2t
–e
– K1t
}
( K1 – K2 )
♣8) Xm1f, the mass of metabolite, Fosinoprilat, in feces. A = none(no drug goes there)
X
♣9) Cp, the plasma concentration of parent drug, Fosinopril C =  -----0- e – K1t
Vd
k X
♣10) Cpm1, the plasma concentration of metabolite, Fosinoprilat. m1 0
-{e
A = ------------------------------- –K2t
–e
– K1t
}
( K1 – K2 )V d
Find the value of:

♦11) dR/dT I = -0.6 mm Hg/hr
♦12) dR/d(ln(Cpm1)) D = 8.2 mm Hg
♦13) d(ln(Cpm1))/dT C = -0.074 hr-1

♥14) ku, the renal excretion rate constant of parent drug, Fosinopril, in plasma. A = none(no drug goes there)
♥15) km1, the metabolism rate constant of parent drug, Fosinopril, in plasma. F = 0.5 hr -1
♠16) kmu1, the renal excretion rate constant for metabolite, Fosinoprilat, in plasma. B = 0.037 hr -1
♠17) km2, the metabolism rate constant for the metabolite of Fosinoprilat in plasma. B = 0.037 hr -1
♥18) K1, the elimination rate constant of parent drug in plasma , the summation of all processes which remove Fosinopril. F = 0.5 hr -1
♠19) K2, the elimination rate constant of metabolite in plasma , the summation of all processes which remove Fosinoprilat. D = 0.074 hr -1
For fosinoprilat IV, find the value of :

♥20) AUC(fosinoprilat) F = 5676 ng/mL
♥21) AUMC(fosinoprilat) J = 76700 mg/mL*hr2

♥22) MRT(fosinoprilat) H = 13.5 hr

♥23) Ke for fosinoprilat (hr-1) D = 0.074 hr -1

♥24) T 1 ⁄ 2 for Fosinoprilat (hr) E = 9.4 hr
♥25) Cp0(fosinoprilat) for iv dose (ng/mL) C = 420 ng/mL

♥26) Vd for Fosinoprilat (L) J = 18 L
♥27) Cp of Fosinoprilat at eight hours after the IV dose B = 232 ng/mL
For fosinoprilat given as IV fosinopril, dXm1/dt, find the value of :

♠28) AUC(fosinoprilat)(mg) F = 10 mg
♠29) AUMC(fosinoprilat) A = 155 mg*hr
♠30) MRT(fosinoprilat) I = 15.5 hr
♠31) K2 for fosinoprilat (hr-1) D = 0.074 hr -1

♠32) T ? for Fosinoprilat (hr) E = 9.4 hr
♠33) K1 for fosinopril (hr-1) F = 0.5 hr -1

14.9 Omeprazole
14.9.1 OMEPRAZOLE DATA

Omeprazole (mw: 345.42) is a gastric proton-pump inhibitor which decreases gastric acid secretion. It is effective in
the treatment of ulcers and esophageal reflux. In normal patients, 20% of the omeprazole is excreted into the feces and
80% of the omeprazole dose is excreted as an inactive metabolite into the urine. In the study by Anderson, et. al., eight
patients were given 20 mg, IV bolus doses of omeprazole. The patients had a mean body weight of 70 kg. Blood and
urine were collected at various intervals throughout the study and the following data was obtained:
TABLE 14-2 Pharmacological Response
% Acid Secretion % Acid Secretion Concentration

Inhibition Time (min) Inhibition (ng/mL)
100 120 74 1
100 240 62 .6
75 330 56 .5
63 360 47 .35
56 375 27 .15
50 390
25 450
10 570
8 600
0 720
TABLE 14-3 Plasma profile of parent and urine profile of metabolite
Intercept = 4 mg/hr
Parent Compound AUMCmet = 96 mg*hr
Urine Collection Metabolite

Time (hr) Cp (ng/mL) Interval (hr) collected (mg)
0.5 336 0-1 1.19
1 205 1-2 2.07
2 75 2-3 2.10
3 28 3-5 3.44
4 10 5-7 2.38
7-9 1.62
9 - 11 1.08
11 - 13 0.72
13 - 15 0.48
16 - 20 0.44

14.9.2 OMEPRAZOLE QUESTIONS

Using LaPlace transforms, from Omeprazole, given by IV bolus, find the equation
for:
1. ♣1) X, the mass of Omeprazole in the body
2. ♣) Xu, the mass of Omeprazole in urine.
3. ♣) dXu/dt, the rate of excretion of Omeprazole in urine.
4. ♣) Xf, the mass of Omeprazole in feces.
5. ♣) Xm, the mass of metabolite of Omeprazole in the body
6. ♣) Xmu, the mass of metabolite of Omeprazole in urine.
7. ♣) dXmu/dt, the rate of excretion of metabolite of Omeprazole in urine.
8. ♣) Xmf, the mass of metabolite of Omeprazole in feces.
9. ♣) Cp, the plasma concentration of parent drug, Omeprazole
10. ♣) Cpm, the plasma concentration of metabolite of Omeprazole.
Find the value of:
11. ♦) dR/dT = slope of the Pharmacological response vs. time profile (% / hr)
12. ♦ ) dR/d(lnC) = slope of the Pharmacological response vs concentration profile (%)
13. ♦) d(lnC)/dt = slope of the concentration vs time profile (hr-1 )

14. ♥♠ ) kr = urinary excretion rate constant Omeprazole (hr-1 )
15. ♥♠) kf = fecal excretion rate constant Omeprazole (hr-1 )
16. ♥♠) km = rate of metabolism of Omeprazole in the body (hr-1 )
17. ♥♠) K1 = elimination rate constant of Omeprazole in the body; the summation of all of the ways that it
is removed from the body. (hr-1 )
18. ♥♠) T1/2 of Omeprazole in the body (hr)
19. ♥♠) X0 = Mass of Omeprazole in the body at time 0 (mg)
20. ♥♠) Xinf = Mass of Omeprazole in the body at time infinite time (mg)
21. ♥♠) Xuinf = Mass of unchanged Omeprazole in the urine at infinite time (mg)
22. ♥♠) Xfinf = Mass of unchanged Omeprazole in the feces at infinite time (mg)
23. ♥♠) V = Volume of distribution of Omeprazole (L)
24. ♥♠) Cp0 = Concentration of Omeprazole in the body at time 0. (mic/L)
25. ♥♠) AUCiv = Area under the plasma concentration of Omeprazole vs time curve of the IV
dose (mic/L*hr)
26. ♥♠) First trapazoid of the AUCiv (mic/L*hr)
27. ♥♠) Last trapazoid of the AUCiv (mic/L*hr)
28. ♥♠) AUMCiv = Area under the first moment of the plasma concentration of Omeprazole vs
time curve of IV dose (mic/L*hr2 )
29. ♥♠) MRTiv = Mean Residence time of Omeprazole given as the IV dose (hr)
30. ♥♠) Xm = Mass of metabolite in the body at time = 0 (mg)

31. ♥♠) Xminf = Mass of the metabolite in the body at infinite time. (mg)
32. ♥♠) Vm = Volume of distribution of the metabolite in the body (L)
33. ♥♠) Cpm = Concentration of metabolite in the body at time = 0 (mic/L)
34. ♥♠) AUCmet = Area Under the Curve of the metabolite excretion rate vs time profile (mg)
35. ♥♠) Xmu0 = Mass of metabolite in urine at time = 0 (mg)
36. ♥♠) Xmuinf = Mass of metabolite in urine at time = infinity (mg)
37. ♥♠) Xmf0 = Mass of metabolite in feces at time = 0 (mg)
38. ♥♠) Xmfinf = Mass of metabolite in feces at time = infinity (mg)
39. ♥♠) Kmu = Rate constant of excretion of metabolite into urine (hr-1 )
40. ♥♠) Kmf = Rate constant of excretion of metabolite into feces (hr-1 )
TABLE 14-4 Omeprazole Answer Pool
Minus Small Med Large Equations More Equations
A -0.8 0 1 100 None km X0 –K 2 t – K1 t

- (e
--------------------------------- –e )
( K 1 – K 2 )V dm
B -1 0.1 2 147 – K1 t km X0 –K 1 t – K2 t
X0 e - (e
--------------------------------- –e )
( K 1 – K 2 )V dm
C -2 0.2 4 210 X 0  –K 1 t
 ------ k mu X 0 –K 2 t – K1 t
- e - (e
--------------------------------- –e )
 Vd ( K 1 – K 2 )V dm
D -4 0.3 8 223 ku X0 e
–K 1 t k mu k m X 0 – K 2 t – K1 t
----------------------- (e –e )
( K1 – K 2 )
E -8 0.4 10 372 kf X0 e
– K1 t k mu k m X 0 – K 1 t – K2 t
----------------------- (e –e )
( K1 – K 2 )
F -10 0.5 16 444 ku 

 ------ –K1 t k mu X 0 –K 2 t – K1 t
X (1 – e ) ----------------------- (e –e )
K  0 ( K1 – K 2 )
1
G -16 0.6 20 556 kf 

 ------ –K1 t
k mf k m X 0  1 – e – K2 t  1 – e – K 1 t
 K  X0 ( 1 – e )
-----------------------  --------------------- –  ---------------------
1 ( K1 – K 2 )  K 2   K 1 
H -20 0.7 25 643 k m X0 –K 2 t – K1 t k mf k m X 0  1 – e – K1 t  1 – e – K 2 t

----------------------- (e –e )  --------------------- –  ---------------------
( K1 – K 2 ) -----------------------
( K1 – K 2 )  K 1   K 2 
I -25 0.8 36 756 k m X0 –K 1 t – K2 t k mu k m X 0  1 – e – K2 t  1 – e – K 1 t

----------------------- (e –e ) -----------------------  --------------------- –  ---------------------
( K1 – K 2 ) ( K1 – K 2 )  K 2   K 1 

Minus Small Med Large Equations More Equations
J -36 0.9 44 893 k mu X 0 –K2 t – K1 t k mu k m X 0  1 – e – K1 t  1 – e – K 2 t

----------------------- (e –e )
( K1 – K 2 ) -----------------------  --------------------- –  ---------------------
( K1 – K 2 )  K 1   K 2 
A Missing Information. Can not answer question with information available

14.9.3 OMEPRAZOLE SOLUTIONS
kf
Xf X
km
kmu
Xm Xmu
80 80
70 70
-1 0
60 60
Response
Response
50 50
40 40
30 30
20 20
320 340 360 380 400 420 440 460 10
Concentration 10
Time (min)
10
10
Concentration
Concentration
10 10
10
0 2 4 6 8 10 12 10
0 5 10 15 20
Time (hr) Time (hr)

– K1 t
1. (B) X = X0 e
2. (A) X u = 0 See model.
dX u
3. (A) --------- = 0 See model.
dt
k
Xf =  ------f  X 0 ( 1 – e
–K 1 t
4. (G) )
K 
1
km X0 –K 2 t – K1 t
5. (H) X m = ----------------------- (e –e )
( K1 – K 2 )
k mu k m X 0  1 – e – K2 t  1 – e – K1 t
6. (I) X mu = -----------------------  --------------------- –  ---------------------
( K 1 – K2 )  K2   K1 
dX mu k mu k m X 0 – K2 t – K 1 t
7. (D) ------------- = ----------------------- (e –e )
dt ( K 1 – K2 )
8. (A) X mf = 0 See model.
X
C p =  ------0- e
–K 1 t
9. (C)  Vd
km X 0 – K2 t –K 1 t
10.(A) -(e
C pm = --------------------------------- –e )
( K 1 – K 2 )V dm
dR – 0.4% – 25%
11.(I) ------- ≅ ------------------ ≅ -------------- Estimate from graph. Between 20-80% of maximal
dt minute hr
response ONLY!
dR 74%-57% 17%
12.(H) --------------- = ---------------------------------------------- = ------------- ≅ 25% Points taken from sample graph.
d ln C p ng ng 0.693
ln 1.0 ------ – ln 0.5 ------
ml ml
d ln C p dR d ln C – 25% 1 –1
13.(B) --------------- = ------- × ---------------p = -------------- × ----------- = – 1 hr
dt dt dR hr 25%
14.(A) kr = 0 See model.
∞ –1
Xf K 1 4mg ⋅ 1hr
15.(C) k f = -------------
- = ----------------------------- = 0.2hr
–1
Also, kf is 20% of K1 , or 20% of 1hr-1 =
X0 20mg
0.2hr-1
–1 –1 –1
16.(I) k m = K 1 – k f = 1hr – 0.2hr = 0.8hr if you have k f .or
∞ –1
X mu K 1
k m = ---------------- = 16mg ⋅ 1hr = 0.8hr – 1
-------------------------------- . Also, km is 80% of K1 , or 80% of 1hr-1 =
X0 20mg
0.8hr-1
– d ln C –1
17.(A) K 1 = ------------------p = 1hr
dt
18.(H) t 1 ⁄ 2 = 0.693
------------- = 0.693 → 0.7hr
K1
19.(G) X 0 = 20mg Read introduction.
20.(A) X inf = 0 See model.
21.(A) Xu ( inf ) = 0

20
22.(C) X f ( inf ) = --------- × 20mg = 4mg 20% of parent excreted in feces (read introdction).
100
23.(I) Dose- ≈ -----------------

V d = ------------ 20mg ≈ 20 , 000µg- ≈ 36L
------------------------
C p0 ng µg
556 -------- 556 ------
mL L
24.(G) ng- ≈ 556 µg

C p0 ≈ 556 ------- ------ From graph.
mL L
C p ( n ) + C p ( n + 1 ) C p ( last ) C p0
25.(G) AUC IV = ∑ 
---------------------------------------
2 
∆t + ------------------
K1
or AUC IV = --------
K1
-
AUC IV =  ------------------------ × 0.5 +  ------------------------ × 0.5 +  --------------------- × 1 +  ------------------ × 1 +

556 + 336 336 + 205 205 + 75 75 + 28
or
2 2 2 2
 28 µg ⋅ hr
------------------ × 1 + ------ = 578.75 → 556 -----------------
+ 10 10
 2  1 L
ng
556 --------
mL = 556 µ
AUC IV = ----------------- ⋅ hr
-------------
1hr L
26.(D)  556 + 336- × 0.5 = 223 µg

----------------------- ⋅ hr-
----------------
 2  L
10 µg ⋅ hr
27.(E) ------ -----------------
1 L
tn Cp (n ) + tn + 1 Cp (n + 1 ) C p ( last ) tlast C p ( last )
 -------------------------------------------------------
- ∆t + ------------------
28.(G) AUMC IV = ∑  2  2
+ ----------------------------
K1
( K1 )
( 556 ) + 0.5 ( 336 -) × 0.5 +  0.5

AUMC IV =  0-------------------------------------------- ( 336 ) + 1 ( 205 ) × 0.5 +  1-------------------------------------
--------------------------------------------- ( 205 ) + 2 ( 75 ) × 1 +
 2   2   2 
2
( 75 ) + 3 ( 28 )
 2---------------------------------- 3 ( 28 ) + 4 ( 10 ) 10 4 ( 10 ) µg ⋅ hr
× 1 +  ---------------------------------- × 1 + ------ + -------------- = 541.75 → 556 -------------------
 2   2  2 1 L
1
2
556 µg ⋅ hr
-------------------
29.(A) MRT IV AUMC L
= ------------------ ≈ ----------------------------- ≈ 1hr or 1 = -------------
MRT IV = ------ 1 - = 1hr
556 µg ⋅ hr-
AUC K1 –1
---------------- 1hr
L
30.(A) Xm 0 = 0 See model.
31.(A) X m ( inf ) = 0 See model.
32.(A) V dm = Can not determine from information given. Need C pm information.
33.(A) C pm0 = 0 See model.
∑ Xmu
80
34.(F) AUC met = = --------- × 20mg = 16mg . AUC is equal to all drug which goes
100
through compartment, which is 80% of the 20 mg dose, or 16 mg (read intro-
duction).
35.(A) X mu0 = 0 See model.
36.(F) 80- × 20mg = 16mg
X mu ( inf ) = -------- 80% of the 20 mg dose is found as metabolite in
100
urine (Read introduction).
37.(A) X mf0 = 0 See model.
38.(A) X mf ( inf) = 0 See model.

39.(C) k mu = K 2 = 0.2hr –1 = is k small from urine data graph because k l arg e ≅ 1hr
–1
which is K1 .
40.(A) K m f = 0 See model.

14.10 EXP3312, an Experimental Drug

Wong N, Wong P. (J Pharm Pharmacol 1996; 48: 492-497) investigated the phar-
macological and pharmacokinetic response of EXP3312
14.10.1 EXP3312 DATA
EXP3312 is a non-peptide angiotension II AT1-receptor antagonist which has

potential as an oral hypertensive drug. EXP3312 a pro-drug is metabolized to an
active metabolite M1. Experiments with rats show M1 is the active drug. As with
all angiotension II antagonists EXP3312 blocks the renin-angiotension system.
EXP3312 is a synthesized analog of Losartin, but EXP3312 has greater oral
hypotensive potency and has promise in future treatment of human renal hyperten-
sion. EXP3312 is still an experimental drug without all pharmacological responses
having been explored. However, we may assume the drug is completely metabo-
lized to the active metabolite (M1). Thereafter, the active metabolite (M1) is
excreted unchanged in the urine.
The following pharmalogical data was obtained using pithed (spinal tap) rats with
an average weight of 350 g. The concentration of drug in each rat is based on aver-
age weights of the rats. The measured responses of decrease in mean arterial pres-
sure (MAP decrease) are shown below.The researchers supplied graphical data of
mean arterial pressure in conscious renal hypertensive rats. M1 metabolite was
measured and the results are also shown in the table below.
TABLE 14-5
Response (mm Hg) M1 administration (mg/kg) Response (mm Hg) Time (hr)
(MAP) decrease I.V. bolus (MAP) decrease
25 0.01 60 0
36.5 0.03 57.4 1
48.5 0.1 54.7 2
59 0.3 49.3 4
44.5 6

The parent compound EXP3312 and metabolite M1 levels were measured in the
plasma over time. The data obtained from the active M1 metabolite and the inac-
tive partent drug EXP3312 are shown below. The standard dose for each rat was
0.3mg/kg.
TABLE 14-6
EXP3312 M1
time (hr) Cp (mic/mL) Cp (mic/mL)
0.15 0.32
0.3 0.59
0.5 0.4
1 0.26 1.34
2 0.11 1.61
3 0.045
4 1.26
6 0.81
10 0.3
12 0.18
I = 3.81 mic/mL
Use the following data was obtained when an intravenous infusion of a different
dose was given to an average rat over 45 minutes.
TABLE 14-7
time (hr) Plasma concentration

(mic/mL)
0.25 0.139
0.5 0.26
0.75 0.35
1 0.29
2 0.12
3 0.05

14.10.2 EXP3312 & M1 QUESTIONS:

Using the information given find the pharmacokinetic parameters (CHECK
YOUR UNITS!!!!!!):
1. dR/dt of M1 active metabolite (mmHg/hr)
2. dR/d(lnCp) active metabolite (mmHg)
3. d(lnCp)/dt of M1active metabolite (hr-1)
4. The slope of Cp vs: t of EXP3312 on semi-log paper (hr-1)
5. The slope of terminal portion of dXmu/dt vs: t (mid) on semi-log paper (hr-1)
6. The slope of stripped portion of Cpm vs: t or (Concentration of M1 vs: t) on semi-log paper
(hr-1)
7. The equation for X in the body.
8. The equation for Xm or M1 in the body.
9. K1 (elimination rate constant of EXP3312) (hr-1)
10. ku (urinary excretion rate constant of EXP3312) (hr-1)
11. km (metabolism rate constant of M1 (hr-1)
12. kmu (urinary excretion rate constant of M1 (hr-1)
13. Cp0 (Initial IV bolus concentration of EXP3312) (mic/ml)
14. Vd of EXP3312 (L)
15. Vdm of M1 (L)
16. AUC (Cp vs: t for EXP3312 by IV bolus) (mic/mL*hr))
17. AUMC (t*Cp vs: t for EXP3312 by IV bolus) (mic/mL* hr2))
18. MRT for EXP3312 (hr)
19. AUC (dXu/dt vs: t (mid) for EXP3312 by IV bolus) (mg)
20. AUC (dXmu vs: t (mid) for M1) (mg)
21. X0 (EXP3312 in the body at time zero) (mg)
22. Xmu 0 (M1in the urine at time zero) (mg)
23. Xm0 (M1 in the body at time zero) (mg)
24. X at 2hr (EXP3312 in the body at 2 hr.) (mg)
25. Xm at 2hr (M1 in the body at 2 hr.) (mg)
26. Xinf (EXP3312 in the body at infinite time) (mg)
27. Xuinf (EXP3312 in the urine at infinite time) (mg)
28. Xminf (M1in the body at infinite time) (mg)
29. T1/2 (EXP3312) (hr)
30. Clearance of EXP3312 (L/hr)
EXP3312 Infusion Questions:

31. K (elimination rate constant of EXP3312) (hr-1)

32. T1/2 (EXP3312) (hr)
33. Volume of distribution (L/kg)
34. Clearance (L/hr/kg)
35. How long will it take to reach 95% steady state? (hr)
36. Q (infusion rate) (mg/hr)
37. Find the plasma concentration if the infusion in Table 14-7 on page 58 was discontinued at 5
hours instead of 45 minutes. (mic/mL)
38. Find the time need for the concentration to drop to 0.23 mic/mL after the infusion in question 37
is discontinued (hours).
39. Determine the new infusion rate necessary to maintain a plasma concentration of Cpss 1.0 mic/
mL of the average rat. (mg/hr)
40. Find a loading dose for the average rat which would give the Cpss of 1.0 mic/mL immediately
(mg)

TABLE 14-8 Answer Pool
Minus Small Big Bigger Equations Equations

ones ones ones ones
A -0.121 0 0.55 1.05 None km X0 – K2 t –K 1 t
---------------------------------- (e –e )
( K 1 – K 2 )Vd m
B -0.26 0.019 0.62 1.15 –K 1 t km X0 – K1 t –K 2 t

X0 e ---------------------------------- (e –e )
( K 1 – K 2 )Vd m
C -0.391 0.039 0.72 1.32 X0  –K1 t k mu X 0

 ------
- e - (e
---------------------------------
– K2 t
–e
–K 1 t
)
 Vd ( K 1 – K 2 )V dm
D -0.567 0.063 0.80 1.69 –K 1 t k mu k m X 0 –K 2 t – K1 t

kuX 0 e ----------------------- (e –e )
( K 1 – K2 )
E -0.621 0.105 0.83 2.63 – K1 t k mu k m X 0 –K 1 t – K2 t

kf X0 e ----------------------- (e –e )
( K 1 – K2 )
F -0.866 0.146 0.866 3.5 ku 

 ------ X (1 – e
– K1 t
)
k mu X 0
----------------------- (e
– K2 t
–e
– K1 t
)
K  0 ( K 1 – K2 )
1
G -1.112 0.169 0.94 4.17 kf 

 ------ X (1 – e
– K1 t
) k mf k m X 0  1 – e –K 2 t  1 – e –K 1 t
K  0 -----------------------  --------------------- –  ---------------------
1 ( K1 – K 2 )  K 2   K1 
H -1.981 0.26 0.95 4.83 km X0

----------------------- (e
–K2 t
–e
–K 1 t
) k mf k m X 0  1 – e –K 1 t  1 – e –K 2 t
( K1 – K 2 ) -----------------------  --------------------- –  ---------------------
( K1 – K 2 )  K 1   K2 
I -2.63 0.42 0.96 7.2 km X0

----------------------- (e
–K1 t
–e
–K 2 t
) k mu k m X 0  1 – e –K 2 t  1 – e –K 1 t
( K1 – K 2 ) -----------------------  --------------------- –  ---------------------
( K1 – K 2 )  K 2   K1 
J -3.71 0.48 0.99 10.1 k mu X 0 – K2 t –K 1 t

----------------------- (e –e ) k mu k m X 0  1 – e –K 1 t  1 – e –K 2 t
( K1 – K2 ) -----------------------  --------------------- –  ---------------------
( K1 – K 2 )  K 1   K2 
This exam is given early at the request of those students who had conflict with the time agreed upon. They signed a
document stating that they would not share their experience with anyone under pain of prosecution for adademic mis-
conduct which will result minimally in an “F” for the course. You also must sign this document.
I ___________________________________________ did not comunicate in anyway anything at all regarding this
exam nor give or receive any assistance during the exam upon my honor as a health professional and under pain of
prosecution for adademic misconduct.
Signed__________________________________________________________Date__________________

14.11 Graph Paper
0 1
0
CHAPTER 15 Practice Exams: Exam 2

Practice Exams: Exam 2
15.1 Nifedipine: Exam 2

Nifedipine (Procardia @) is a calcium channel blocker which specifically inhibits potential-dependent channels not
receptor-operated channels, preventing calcium influx of cardiac and vascular smooth muscle (coronary, cerebral).
Calcium channel blockers reduce myocardial contractility and A-V node conduction by reducing the slow inward cal-
cium current. They are indicated in angina, cardiac dysrhythmias, and hypertension among others. Nifedipine
appears to be metabolized entirely into an inactive metabolite, an acid and subsequently further metabolized to a lac-
tone. Both the acid and the lactone are excreted into the urine and the feces.
Hepatic blood flow in normals is 1.6 L/min

Renal blood flow in normals is 1.2 L/min
Echizen and Eichelbaum (Clin Pkin 1986; 11:425-49) and Kleinbloesem et al (Clin Pcol Therap 1986; 40: 21-8)
reviewed the pharmacokinetics of Nifedipine. While the drug is not routinely given by IV bolus and does not strictly
conform to a one compartment model, let's treat the data as if those problems can be ignored. The following data is
offered for evaluation:
TABLE 1-1. Nifedipine IV Bolus Profile
Time (hr) Cp (mcg/L) Cm1 (mcg/L) Xm1f (mg) Xm1u (mg) Xm2f (mg) Xm2u (mg)
0.5 24.7
1 44.4
2 139 71.8 .14 .59
4 65.6 96.5 .44 1.83 .028 .11
6 31.1 100 .77 3.25 .073 .29
8 14.6 94.7 1.1 4.65 .135 .54
12 76.5 1.69 7.10 .291 1.15
24 34 2.77 11.63 .75 2.95
7 days 3.6 15.1 1.3 5.0
TABLE 1-2 Nifedipine Oral information
Brand Generic
Route IV Oral Capsule Oral Capsule
Dose (mg) 25 10 10
AUC (ug/L*hr) 785 236 204
AUMC (ug/L*hr2 ) 2093 866 816

Practice Exams: Exam 2 : Nifedipine: Exam 2
15.1.1 NIFEDIPINE QUESTIONS:

Find: 21) MRT (oral generic capsule) (hr)
1) MRT iv (hr) 22) MAT (oral generic capsule) (hr)
2) Ke (elimination rate constant) for Nife- 23) Ka, the apparent absorbtion rate con-
dipine (hr-1 ) stant, for the generic capsule (hr-1 )
3) T 1/2 for Nifedipine 24) Peak time for the generic capsule (hr)
4) Cp0 for iv dose (ug/L) 25) Cpmax , the maximum concentration
of the generic oral capsule give as a single
5) Vd for Nifedipine (L) dose (ug/L)
7) Cp of Nifedipine at one hour after the 26) Comparative bioavailability of the oral
IV dose capsules
8) AUC from 0 to one hour for the IV dose Your patient is controlled by 20 mg TID
9) Total Body Clearance of Nifedipine (L/ of the brand name oral capsule when he
hr) is healthy.
10) Renal Clearance of Nifedipine (L/hr) 27) What is his N for that dosing regimen?
11) Hepatic Clearance of Nifedipine (L/hr) 28) Cpssmax for this patient at this dosing
regimen (ug/L)
12) Renal Extraction Ratio
29) Cpssavg for this patient at this dosing
13) Hepatic Extraction Ratio
regimen (ug/L)
14) Absolute bioavailability for the brand
30) Cpssmin for this patient at this dosing
name capsule
regimen (ug/L)
15) MRT (oral brand name capsule) (hr)
You want to maintain his plasma con-
16) MAT (oral brand name capsule) (hr) centrations between 110% of Cpssmax
and 90% of Cpssmin . How would you
17) Ka, the apparent absorbtion rate con-
change the dosage regimen to if your
stant, for the brand name capsule (hr-1 )
patient suffered from:
18) Peak time for the brand name capsule
31) stenosis of the kidney (Fr = 0.67).
(hr)
32) renal failure (Fi = 0.67).
19) Cpmax , the maximum concentration
of the brand name oral capsule give as a 33) stenosis of the liver (Fr = 0.67)
single dose (ug/L)
34) cirrhosis of the liver (Fi = 0.67)
20) Absolute bioavailability for the generic
capsule

TABLE 1-3 Nifedipine Answer Pool

Small Medium Large Dosing changes:
a) 0.00 a) 1.85 a) 59 a) 10 mg once daily
b) 0.05 b) 2.67 b) 85 b) 10 mg BID
c) 0.33 c) 3.67 c) 92.5 c) 10 mg TID
d) 0.375 d) 4.0 d) 101 d) 10 mg QID
e) 0.65 e) 4.32 e) 124 e) 20 mg once daily
f) 0.75 f) 9.3 f) 147 f) 20 mg BID
g) 0.85 g) 18.5 g) 185 g) 20 mg TID (no change necessary)
h) 1.0 h) 32 h) 202 h) 20 mg QID
i) 1.33 i) 38 i) 248 i) 30 mg once daily
j) 1.57 j) 49 j) 294 j) 30 mg BID

15.1.2 NIFEDIPINE SOLUTIONS

MRT iv = 2.67hr 21. Oral generic capsule
1.
MRT = 4hr
–1
2. k e = 0.375hr 22. Oral generic capsule
MAT = 1.33hr
3. T1 ⁄ 2 = 1.85hr
23. Oral generic capsule
4. Cp 0 = 294ug ⁄ L –1
Ka = 0.75hr
5. Vd = 85L 24. Oral generic capsule peak time
6. skip (error in numbering) 1.85hr
7. Cp 1 = 202ug ⁄ L 25. Oral generic capsule

Cp max = 38ug ⁄ L
8. AUC 0 – 1 = 248ug ⁄ L ⋅ hr
26. Comparative bioavailability of the
9. Cl s = 32L ⁄ hr oral capsules B/A:
AUC = 0.86 (ok)
10. Cl r = 0
Peak time = 1.18 (ok)
11. Cl h = 32L ⁄ hr Cpmax = 0.78 (not ok!)
12. Er = 0 27. N = 4.32

ss
13. Eh = 0.33 28. Cp max = 185ug ⁄ L
ss
14. Absolute bioavailability for brand 29. Cp ave = 59ug ⁄ L
name capsule = 0.75
ss
15. Oral brand name capsule 30. Cp min = 9.3ug ⁄ L
MRT = 3.67hr 31. No change
16. Oral brand name capsule 32. No change
MAT = 1.0hr 33. No change
17. Oral brand name capsule 34. No change
–1
Ka = 1.0hr
18. Oral brand name peak time
1.57hr
19. Oral brand name
Cp max = 49ug ⁄ L
20. Absolute bioavailability for
generic = 0.65

Practice Exams: Exam 2 : Valproate: Exam 2
15.2 Valproate: Exam 2

All questions are internally consistent. Information gained in any one can be used in all others. Note, however, there
is a change in patient status midway through.
Valproate is a carboxylic acid anticonvulsant. Its activity may be related, at least in part, to increase concentra-
tions of the neurotransmitter inhibitor gamma aminobutyric acid in the brain. It is used alone or in combination
with other anticonvulsants. in the prophylactic management of petit mal. It appears to be almost entirely cleared
by liver function with negligible amounts excreted into the urine unchanged. It comes as soft gelatin capsules of 250
mg and enteric coated tablets 250 and 500 mg. The therapeutic range for valproate appears to be between 20 and 100
mic/ml. The volume of distribution is 0.19 L/Kg and your patient is 70 kg.
TABLE 1-4
IV bolus Brand Generic

Dose (mg) 500 250 250
AUC (mg/L*hr) 594 273 253
AUMC(mg/L*hr ) 2 9428.6 4605.5 4184.6
Tpeak (hr) 2.95
Cpmax 14.35
Bioavailability (f) 1.0 .92

15.2.1 VALPROATE QUESTIONS

1) Calculate the MRTiv of Valproate (hr).
a) 11 b) 15.87 c) 16.54 d) 16.87 e) 17.08
2) Calculate the rate constant of elimination (hr-1 ) in normals ?

a) 0.091 b) 0.063 c) 0.060 d) 0.0593 e) 0.0585
3) Calculate the half life of Valproate (hr)?

a) 7.6 b) 11 c) 11.5 d) 11.7 e) 11.8
4) Calculate the hepatic clearance of valproate (L/hr).

a) 0.0084 b) 0.063 c) 0.84 d) 1.25 d) 2.5
5) Calculate the hepatic extraction ratio of valproate.

a) 0.0063 b) 0.0084 c) 0.063 d) 0.084 e) 0.84
6) What is the maximum N for multiple dosing of Valproate?

a) 0.78 b) 1.65 c) 2.12 d) 2.32 e) 2.5
7) What is the maximum acceptable dosing interval for normal patients (hr)?
a) 8 b) 12 c) 18 d) 24 e) 25.5
8) What is the N if we are going to dose TID?

a) 0.63 b) 0.727 c) 0.842 d) 1.25 e) 1.42
9) If you dosed this patient 500 mg BID with the brand name product, what would be your maximum concentration at
steady state (mg/L)?
a) 87.3 b) 70.9 c) 65.2 d) 52.8 e) 45.8
10) What would be your minimum concentration at steady state (mg/L)?

a) 52.8 b) 32.7 c) 30.1 d) 27.1 e) 22.9

11) What would be your average concentration at steady state (mg/L)?

a) 63.8 b) 49.8 c) 47.7 d) 45.8 e) 34.4
12) What loading dose would you give to get to Cpss right away (mg)?
a) 250 b) 500 c) 750 d) 1000 e) 1500
13) If you changed the dosage regimen to 250 mg QID, what would happen to the Cpssmax, Cpssave, Cpssmin?
a) Cpssmax - up, Cpssave - up, Cpssmin - up
b) Cpssmax - down, Cpssave - down, Cpssmin - down
c) Cpssmax - same, Cpssave - same, Cpssmin - same
d) Cpssmax - up, Cpssave - same, Cpssmin - down
e) Cpssmax - down, Cpssave - same, Cpssmin - up
14) Calculate f, the absolute bioavailability of the generic product.

a) 0.67 b) 0.75 c) 0.85 d) 0.93e) 1.0
15) Calculate the comparative bioavailability of the generic product.
a) 0.67 b) 0.75 c) 0.85 d) 0.93e) 1.0
16) Calculate the MRToral of the generic product.
a) 11 b) 15.87 c) 16.54 d) 16.87 e) 17.08
17) Calculate the MAT of the generic product.

a) 0.67 b) 0.75 c) 0.85 d) 0.93e) 1.0
18) Calculate the Ka of the generic product.

a) 1.5 b) 1.33 c) 1.18 d) 1.08 e) 1.0
19) Calculate the peak time of the generic product.

a) 2.21 b) 2.45 c) 2.59 d) 2.76 e) 2.95
20) Calculate the Cpmax of the generic product.

a) 8.1 b) 9.3 c) 10.7 d) 12.6 e) 14.4
21) Is the generic product bioequivalent?

a) Yes
b) No, because the comparative bioavailability is outside the federal guidelines.
c) No, because the ratio of the peak times is outside the federal guidlines.
d) No, because the ratio of the Cpmax s is outside the federal guidlines.
e) No, because the generic fails more than one of the required comparisons.
In patients who are also currently on phenobarbital their intrinsic clearance of valproate increases by 50% as the phe-
nobarbital induces the enzymes which metabolize valproate. Further questions refer to this condition.
22) Calculate his new clearance.

a) 0.0084 b) 0.063 c) 0.84 d) 1.25 d) 2.5
23) Calculate his new K.

a) 0.095 b) 0.084 c) 0.063 d) 0.059 e) 0.042
24) Calculate his new maximum acceptable dosing interval (hr).

a) 8 b) 12 c) 17 d) 18 e) 24
25) What dosage regimen would you recommend to try to maintain his plasma concentrations within 110% of the max-
imum and 90% of the minimum concentrations attained when he was normal?
a) 750 mg BID b) 500 mg TID c) 750 mg TID d) 250 mg QID e) 500 mg QID

15.2.2 VALPROATE SOLUTIONS

Practice Exams: Exam 2 : Methyl phenidate
15.3 Methyl phenidate

Methyl phenidate (MP) (Ritalin@) is an effective stimulant in the treatment of narcolepsy in adults and attention deficit
syndrome in children. It is entirely metabolized to the inactive metabolite, Ritalinic Acid (RA), by the liver which is
subsequently excreted unchanged into the urine. The following information was obtained from a 70 Kg male.
QH = 24 mL/min/Kg
QR = 19 mL/min/Kg
TABLE 1-5 Ritalin Data
Brand
IV Name Generic
Dose (mg) 10 20 20
AUC (ug/ml*hr) 0.20 0.04 0.035
AUMC (ug/ml*hr2 0.32 0.14 0.1225
TABLE 1-6 Ritalin Answer Pool
Itty- Bitty Tiny Puny Small Medium Large Words
a 0 0.016 0.1 1.1 10 100 yes

b 0.00016 0.0251 0.125 1.6 20 125 no, Ratio of Tps
c 0.0005 0.035 0.25 1.75 30 225 no, Ratio of Cmaxs
d 0.00074 0.042 0.35 1.9 40 375 no, Ratio of AUCs
e 0.00084 0.05 0.42 2.6 50 435 no, Ratio of AUMCs
f 0.0016 0.067 0.53 3.5 60 550 no, more than one criterion
g 0.005 0.075 0.625 4.2 70 675 20 mg TID
h 0.0074 0.0875 0.727 5.0 80 750 20 mg BID
i 0.0084 0.091 0.875 7.27 90 875 20 mg QD
j 0.0090 0.096 0.91 8.75 96 995 20 mg QID

15.3.1 METHYL PHENIDATE QUESTIONS:

1) MRT iv (hr) 25) Cpmax , the maximum concentration of
the generic oral tablet give as a single dose
2) Ke (elimination rate constant) for
(ug/mL)
Ritalin (hr-1 )
26) Comparative bioavailability of the oral
3) T 1/2 for Ritalin (hr)
tablets
4) Cp0 for iv dose (ug/mL)
27) Are the tablets bioequivalent?
5) Vd for Ritalin (L)
Your patient is controlled by 20 mg TID of
6) Cp of Ritalin at one hour after the IV the brand name oral tablet when he is
dose healthy. For This patient and this dosage
regimen, what is his:
7) AUC from 0 to one hour for the IV dose
28) N ?
8) Total Body Clearance of Ritalin (L/hr)
9) Renal Clearance of Ritalin (L/hr) 29) Cpssmax (ug/mL)
10) Hepatic Clearance of Ritalin (L/hr) 30) Cpssavg (ug/mL)
11) Intrinsic Hepatic Clearance of Ritalin 31) Cpssmin (ug/mL)

(L/hr) You want to maintain his plasma concen-
12) Renal Extraction Ratio trations between 110% of Cpssmax and 90% of
Cpssmin . How would you change the dosage
13) Hepatic Extraction Ratio regimen to if your patient suffered from:
14) Absolute bioavailability for the brand (in no case was there a change in Vd)
name tablet
32) stenosis of the kidney (Fr = 0.67)?
15) MRT (oral brand name tablet) (hr)
33) renal failure (Fi = 0.34)?
16) MAT (oral brand name tablet) (hr)
34) stenosis of the liver (Fr = 0.67)?
stant, for the brand name tablet (hr-1 ) 35) cirrhosis of the liver. (Fi = 0.67)?
18) Peak time for the brand name tablet 36) treatment with phenobarbital (Fi =
(hr) 1.33)?
19) Cpmax , the maximum concentration of
the brand name oral tablet give as a single
dose (ug/mL)
tablet
21) MRT (oral generic tablet) (hr)
22) MAT (oral generic tablet) (hr)
stant, for the generic tablet (hr-1 )
24) Peak time for the generic tablet (hr)

15.3.2 METHYL PHENIDATE SOLUTIONS:

1. MRT iv = 1.6hr 19. Brand name -
Cp max = 0.0084ug ⁄ mL
–1
2. k = 0.625hr
20. Generic - f = 0.0875
3. T1 ⁄ 2 = 1.1hr
21. Generic - MRT = 3.5hr
4. Cp 0 = 0.125ug ⁄ mL 22. Generic - MAT = 1.9hr
5. Vd = 80L –1
23. Generic - Ka = 0.53hr
6. Cp 1 = 0.067ug ⁄ mL
24. Generic - T peak = 1.75hr
7.
25. Generic -
AUC 0 – 1 = 0.096ug ⁄ mL ⋅ hr
Cp max = 0.0074ug ⁄ mL
8. Cl s = 50L ⁄ hr 26. Comparative bioavailability =
0.875
9. Cl r = 0
27. Yes, the tablets are bioequivalent -
10. Cl h = 50L ⁄ hr all parameters are within federal guide-
lines.
11. Cl int = 100L ⁄ hr
28. N = 7.27
12. Er = 0 ss
29. Cp max = 0.0251ug ⁄ mL
13. Eh = 0.53 ss
30. Cp avg = 0.005ug ⁄ mL
14. Brand name - f = 0.1
ss
31. Cp min = 0.00016ug ⁄ mL
15. Brand name - MRT = 3.5hr
32. 20 mg TID
16. Brand name - MAT = 1.9hr
33. 20 mg TID
–1 34. 20 mg BID
17. Brand name - Ka = 0.526hr
35. 20 mg TID
18. Brand name - Tpeak = 1.74hr
36. 20 mg QID


Practice Exams: Exam 2 : Verapamil
15.4 Verapamil
Verapamil is a calcium channel blocker with vasodilatory and antiarrhythmic effects. It is about 95% metabolized by
the liver with the metabolites showing up in the urine and feces.
Hepatic blood flow in normals is 1.6 L/min
Renal blood flow in normals is 1.2 L/min
TABLE 1-7 Verapamil Data
Brand Generic
Route IV Oral Tablet Oral Tablet

Dose (mg) 15 80 80
AUC (ng/mL*hr) 300 480 400
AUMC (ng/mL*hr2 ) 1600 2690 2280
TABLE 1-8 Verapamil Answer Pool
Tiny Small Medium Large Dosing regimens Bioavailability answers
a 0 1.06 26 116 40 mg qd Yes

b 0.063 2.15 46 267 40 mf bid No, tp ratio is not within limits
c 0.188 2.50 47.5 369 40 mg tid No, Cpmax ratio is not within limits
d 0.250 2.70 50 533 40 mg qid No, AUC ratio is not within limits
e 0.270 3.69 56 637 80 mg qd No, f ratio is not within limits
f 0.300 5.33 61.5 830 80 mg bid No, ka ratio is not within limits
g 0.370 5.60 76.5 905 80 mg tid No, ke ratio is not within limits
h 0.693 5.70 83 970 80 mg qid No, MRT ratio is not within limits
i 0.85 6.37 90.5 1160 160 mg qd No, Cl ratio is not within limits
j 0.905 8.30 97 2670 160 mg bid No, more than one of the required ratios are no within limits

15.4.1 VERAPAMIL QUESTIONS

1) MRT iv (hr) 23) Ka, the apparent absorbtion rate con-
stant, for the generic tablet (hr-1 )
2) Ke (elimination rate constant) for Vera-
pamil (hr-1 ) 24) Peak time for the generic tablet (hr)
3) T 1/2 for Verapamil 25) Cpmax , the maximum concentration
of the generic oral tablet give as a single
4) Cp0 for iv dose (ug/L)
dose (ug/L)
5) Vd for Verapamil (L)
26) Comparative bioavailability of the oral
7) Cp of Verapamil at one hour after the IV tablets
dose
Your patient is controlled by 80 mg TID
9) Total Body Clearance of Verapamil (L/ of the brand name oral tablet when he is
hr) healthy.
10) Renal Clearance of Verapamil (L/hr) 28) What is his N for that dosing regimen?
11) Hepatic Clearance of Verapamil (L/hr) 29) Cpssmax for this patient at this dosing
12) Renal Extraction Ratio regimen (ug/L)
13) Hepatic Extraction Ratio 30) Cpssavg for this patient at this dosing
regimen (ug/L)
14) Absolute bioavailability for the brand
name tablet 31) Cpssmin for this patient at this dosing
regimen (ug/L)
You want to maintain his plasma con-
16) MAT (oral brand name tablet) (hr) centrations between 110% of Cpssmax
17) Ka, the apparent absorbtion rate con- and 90% of Cpssmin . How would you
stant, for the brand name tablet (hr-1 ) change the dosage regimen to if your
patient suffered from:
18) Peak time for the brand name tablet
(hr) 32) stenosis of the kidney (Fr = 0.67). (No
change in volume of distribution.)
19) Cpmax , the maximum concentration
of the brand name oral tablet give as a sin- 33) renal failure (Fi = 0.34).(Volume of
gle dose (ug/L) distribution is reduced in this disease to
50% of normal)
tablet 34) stenosis of the liver (Fr = 0.67) (No
change in volume of distribution)
35) cirrhosis of the liver (Volume of Dis-
22) MAT (oral generic tablet) (hr) tribution and the bioavailability are both
doubled while the half life is quadrupled )

15.4.2 VERAPAMIL SOLUTIONS

1. MRT iv = 5.33hr 17. Brand name tablet -
–1
Ka = 3.69hr
–1
2. k e = 0.188hr
18. Brand name tablet - peak time -
3. T1 ⁄ 2 = 3.69hr 0.85hr
19. Brand name tablet -
4. Cp 0 = 56ug ⁄ L
Cp max = 76.5ug ⁄ L
5. Vd = 267L 20. Generic - Absolute bioavailability
6. skip - error in numbering - f = 0.25
7. Cp 1 = 47ug ⁄ L 21. Generic - MRT = 5.7hr
8. AUC 0 – 1 = 50ug ⁄ L ⋅ hr 22. Generic - MAT = 0.37hr

–1
9. Cl = 50L ⁄ hr 23. Generic - Ka = 2.70hr
10. Cl r = 2.50L ⁄ hr 24. Generic - T peak = 1.06hr
11. Cl h = 47.5L ⁄ hr 25. Generic - Cp max = 61.5ug ⁄ L
12. Er = 0.063 26. Comparative bioavailability - 0.85

27. The tablets are not bioequivalent -
13. Eh = 0.49 Correction - should peak time ratio is not within limits.
be added to answer pool
28. N = 2.15
14. Brand name tablet - absolute bio-
ss
availability = 0.30 29. Cp max = 116ug ⁄ L
ss
MRT = 5.60hr 30. Cp avg = 60ug ⁄ L (change in
answer pool)
ss
MAT = 0.270hr 31. Cp min = 26ug ⁄ L
32. No change in dosing regimen - 80
mg TID

33. 40 mg TID 35. 40 mg BID

34. No change in dosing regimen - 80
mg TID

Practice Exams: Exam 2 : Hydromorphone hydrochloride
15.5 Hydromorphone hydrochloride

Hydromorphone hydrochloride is an analog of morphine which has about seven times the analgesic effect of morphine
when given by IV. It is about 90% metabolized. The following data was obtained by Valner et al J.Clin Pcol 21(1981)
152-6:
TABLE 1-9 Hydromorphone hydrochloride Data
Oral tablet Oral tablet

IV Brand Generic
Dose (mg) 2 4 4
AUC (ng/mL*hr) 83 87 65
AUMC (ng/mL*hr2 ) 291 348 292

15.5.1 HYDROMORPHONE HYDROCHLORIDE QUESTIONS

For the IV product, find:
1. MRTiv. (291/83=3.5) 27. R(Bio)= 0.75 fail
2. K. (1/3.5=0.285 You would like to dose your healthy
3. T1/2 (0.693/.285= 2.4 hr) patient using the brand name tablet so
that his plasma concentration is in the
4. Cp0 (AUC*K = 83*0.285= 23.7ng/mL
therapeutic range of 35 to 5 ng/mL.
5. Ku (0.1*0.285=0.029) Find:
6. Km (0.9*0.285=0.256)
28. Nmax (ln(35/5)/ln(2) = 2.8
7. Cls (f*D/AUC=1*2000/83=24L/hr)
29. Taumax (2.8*2.4=6.74 hr
8. Vd (Cls/K=Vd= 24/0.285=84L
30. Maximum acceptable tau = 6
9. Clh (0.9*Cls = 21.6 L/hr
31. N (6/2.4 =2.5)
10. Clr (0.1*Cls = 2.4 L/hr
32. What dosage regimen would you recom-
11. Eh (21.6 / (24 mL/min * 60 min * 70 Kg /
mend? (4mg q6h)
1000mL/L) = 0.2
33. Cpssmax? (30 ng/mL)
12. Er ( 2.4 / ( 10 ml/min * 60 min * 70 Kg /
1000mL/L) = 0.06 34. Cpssavg? (14 ng/mL)
35. Cpssmin? ( 5 ng/mL)
For the Brand name oral tablet, find:

He gets renal stenosis (Fr = 0.5) with no
13. MRT (348/87=4.0)
change in Vd. Find:
14. MAT(4 - 3.5 = 0.5)
36. FClr0.94
15. Ka (1/0.5 = 2.0)
37. Clr*2.3
16. Tp (ln(ka/K)/(ka-K)=1.95/1.715=1.14hr
38. FClh1
17. Absolute bioavailability, f ((87/4)/(83/
2)=0.52 39. Clh*21.6
18. Cpmax (18 ng/mL) 40. FCls.99
41. Cls*23.9
For the Generic oral tablet, find: 42. K*0.284
43. t1/2*2.44
19. MRT ( 292/65=4.5 hr)
44. Nmax 2.8
20. MAT (4.5 - 3.5 = 1 hr)
45. Taumax6.83
21. ka (1/MAT = 1/1=1 hr-1)
46. Maximum acceptable tau 6
22. Tp (ln(1/0.285)/(1-0.285)=1.26/.715=1.76
47. N 2.46
hr
23. Absolute bioavailability, f ((65/4)/(83/ 48. What dosage regimen would you recom-
2)=0.39 mend? 4mg q6h
49. Cpssmax? 30
24. Cpmax (11 ng/mL)
50. Cpssavg? 15
51. Cpssmin? 5.5
Would you consider the oral tablets to
be bioequivalent? Why or why not?
His stenosis of the kidney clears and he
25. No R(Tp) = 1.54 fail
now goes into renal dysfunction
26. R(Cp) = 0.61 fail (Fi=0.5), find:

52. FClr.52 77. Taumax8

53. Clr*1.23 78. Maximum acceptable tau 8
54. FClh2 79. N6
55. Clh*21.6 80. What dosage regimen would you recom-
56. FCls.95 mend? 4 mg q6h
57. Cls*22.8 81. Cpssmax? 32
58. K*0.271 82. Cpssavg? 17
59. t1/2*2.55 83. Cpssmin? 7.5
60. Nmax 2.8
61. Taumax 7.13 His stenosis of the liver clears and he
62. Maximum acceptable tau6 now suffers from liver dysfunction
63. N 2.35
(Fi=0.05), Find:
64. What dosage regimen would you recom- 84. FClr1
mend? 4mg q6h 85. Clr*2.4
65. Cpssmax? 31 86. FClh.56
66. Cpssavg? 15 87. Clh*12
67. Cpssmin? 6.1 88. FCls.6
89. Cls*14.4
His renal dysfunction clears and now he 90. K*.171
suffers from stenosis of the liver 91. t1/2*4.04
(Fr=0.5), Find: 92. Nmax 2.8
68. FClr1 93. Taumax11.3
69. Clr*2.4 94. Maximum acceptable tau8
70. FClh.833 95. N 1.48
71. Clh*18 96. What dosage regimen would you recom-
72. FCls.85 mend?4 mg q8h
73. Cls*20.4 97. Cpssmax? 33
74. K*.243 98. Cpssavg? 18
75. t1/2*2.85 99. Cpssmin?8.4
76. Nmax 2.8


15.6 Fosinopril Sodium

Fosinopril Sodium (MW 585) is a phosphinic prodrug of the angiotensin converting enzyme (ACE) inhibitor fosinopri-
lat (MW 563). After oral administration, fosinopril is slowly and incompletely absorbed, and is converted to the active
fosinoprolat by esterases in the gastrointestinal mucosa and the liver. Unlike other ACE inhibitors, elimination of fosi-
noprilat is divided equally between renal and hepatic pathways. With the IV dose fosinoprilat was given and mea-
sured. With the oral dose fosinopril was given but fosinoprilat was measured. The following information was obtained
from a 70 Kg male. This information was constructed from Kostis et al “Fosinopril: Pharmacokinetics and pharmaco-
dynamics in congestive heart failure” Clin Pcol Ther 58(6) 660-5 (1995); Hui et al “Pharmacokinetics of fosinopril in
patients with various degrees of renal function” Clin Pcol Ther 49(4) 457 -66 (1991)
QH = 24 mL/min/Kg Blood
QR = 19 mL/min/Kg Blood
TABLE 1-10 Fosinopril Data
IV Brand Name Generic

Tablet Tablet
Dose (mg) 7.5 10 10
AUC (ng/ml*hr) 5700 1500 1400
AUMC (ng/ml*hr2) 78000 25000 23100
TABLE 1-11 Fosinopril Answer Pool:
a 0 0.015 0.19 1.3 10 100 yes

b 0.00016 0.0251 0.21 1.6 13.7 142 no, Ratio of Tps
c 0.0005 0.035 0.25 1.75 16.6 192 no, Ratio of Cmaxs
d 0.00074 0.042 0.36 1.9 18 253 no, Ratio of AUCs
e 0.00084 0.05 0.42 2.8 50 387 no, Ratio of AUMCs
f 0.0016 0.067 0.53 3.5 67 402 no, more than one criterion
g 0.005 0.073 0.65 4.0 73 416 10 mg qid
h 0.0064 0.0875 0.72 5.6 84 750 10 mg tid
i 0.0084 0.091 0.84 7.0 93 875 10 mg bid
j 0.0090 0.096 0.93 9.5 96 995 10 mg qd

15.6.1 FOSINOPRIL QUESTIONS

1) MRT for fosinoprilat (hr)
2) Ke for fosinoprilat (hr-1)
3) T ? for Fosinoprilat (hr)
4) Cp0 for iv dose (ng/mL)
5) Vd for Fosinoprilat (L)

6) Cp of Fosinoprilat at one hour after the IV dose
8) Total Body Clearance of Fosinoprilat (L/hr)
9) Renal Clearance of Fosinoprilat (L/hr)
10) Hepatic Clearance of Fosinoprilat (L/hr)
11) Intrinsic Hepatic Clearance of Fosinoprilat (L/hr)
12) Renal Extraction Ratio
13) Hepatic Extraction Ratio
14) Absolute bioavailability for the brand name tablet
16) MAT (oral brand name tablet) (hr)
17) Ka, the apparent absorption rate constant, for the brand name tablet (hr-1 )
18) Peak time for the brand name tablet (hr)

19) Cpmax , the maximum concentration of the brand name oral tablet give as a single dose (ng/mL)
20) Absolute bioavailability for the generic tablet
22) MAT (oral generic tablet) (hr)
23) Ka, the apparent absorption rate constant, for the generic tablet (hr-1 )
24) Peak time for the generic tablet (hr)

25) Cpmax , the maximum concentration of the generic oral tablet give as a single dose (ng/mL)
26) Comparative bioavailability of the oral tablets
Your patient is controlled by 10 mg TID of the brand name oral tablet when he is
healthy. For This patient and this dosage regimen, what is his:
28) N ?

29) Cpssmax (ng/mL)

30) Cpssavg (ng/mL)
31) Cpssmin (ng/mL)
You want to maintain his plasma concentrations between 120% of Cpssmax and 80% of
Cpssmin . How would you change the dosage regimen to if your patient suffered from:
(in no case was there a change in Vd)

32) stenosis of the kidney (Fr = 0.67)?
33) renal failure (Fi = 0.34)?
34) stenosis of the liver (Fr = 0.67)?
35) cirrhosis of the liver. (Fi = 0.67)?
36) treatment with phenobarbital (Fi = 1.5)?

Practice Exams: Exam 2 : Fosinopril Sodium
15.6.2 FOSINOPRIL SODIUM SOLUTIONS

1. MRT = 13.7hr 19. Oral brand name tablet
Cp max = 0.073ng ⁄ mL
–1
2. k = 0.073hr
20. Oral generic tablet absolute bio-
3. T1 ⁄ 2 = 9.5hr availability is 0.19
21. Oral generic tablet
4. Cp 0 = 416ng ⁄ mL
MRT = 16.6hr
5. Vd = 18L 22. Oral generic tablet
6. Cp 1 = 387ng ⁄ mL MAT = 2.8hr
–1
7. AUC 0 – 1 = 402ng ⁄ mL 23. Generic tablet Ka = 0.36hr
24. Generic tablet peak time 5.6hr

8. Cl s = 1.3L ⁄ hr
25. Generic tablet
9. Cl r = 0.65L ⁄ hr Cp max = 0.067ng ⁄ mL
10. Cl h = 0.65L ⁄ hr 26. Comparative bioavailability of the
oral tablets = 0.93
11. Intrinsic Hepatic Clearance is
27. Yes! the tablets are bioequivalent
0.65L ⁄ hr
The AUCs, peak times, and Cp max s are
12. Er = 0.015 all within 20% range.
13. Eh = 0.0064 28. N = 0.84

ss
14. Oral brand name tablet absolute 29. Cp max = 253ng ⁄ mL
bioavailability is 0.21
ss
15. Oral brand name tablet 30. Cp avg = 192ng ⁄ mL
MRT = 16.6hr ss
31. Cp min = 142ng ⁄ mL
16. Oral brand name tablet
MAT = 2.8hr 32. 10 mg TID
17. Oral brand name tablet 33. 10 mg BID

–1 34. 10 mg TID
Ka = 0.36hr
35. 10 mg TID
18. Oral brand name tablet peak time
5.6hr 36. 10 mg QID


15.7 Remoxipride
Remoxipride (MW 296 - Unionized Base pKa 9.4) is a new antipsychotic of the benzamide type (See figure 1). The
pharmacokinetics were studied by Movin-Osswald and Hammarlind-Udenaes (Brit. J Clin Pcol 1991 32(3) 355ff).
Their results are summarized in table 1. The HCl salt of the drug was given (MW 332.5) to these patients in this study
but the drug concentration was reported as the free base in the plasma. In this study, 25% of the Remoxipride was
excreted unchanged, 75% was metabolized. The hepatic and renal blood flow in these patients was 1.5 and 1.2 L/min
respectively. REMEMBER TO PAY ATTENTION TO UNITS.
FIGURE 4-5. Remoxipride
TABLE 1-12 Remoxipride Data
IV bolus Oral Solution Tablet A Tablet B
Dose (mg) 50 100 100
AUMC (umole/ 145 158.7 319.6 282.6

L*hr2 )
AUC (umole/L*hr) 20.9 19.8 37.6 31.4
Tp (hr) 3.6
Cpmax (mg/L) .8
f .75

15.7.1 REMOXIPRIDE QUESTIONS

1) Find the MRT of the IV product (hr).
2) Find the elimination rate constant of remoxipride (hr-1 ).
3) Find the Cp0 of the IV product (mg/L)
4) Find the volume of distribution of the IV product. (L)
5) Find the half life of remoxipride (hr).
6) Find the clearance of remoxipride (L/hr).
7) Find the renal clearance (L/hr).
8) Find the hepatic clearance
9) Find the renal extraction ratio.
10) Find the hepatic extraction ratio.
11) Find the MRT of remoxipride given as the oral solution (hr).
12) Find the MAT of remoxipride given as oral solution (hr).
13) Find the absorption rate constant of remoxipride given as an oral solution (hr-1 ).
14) Find the bioavailability of the oral solution (f).
15) Find the peak time of the oral solution (hr).
16) Find the MRT of remoxipride given as Tablet A, the brand name product.
17) Find the MAT of remoxipride given as Tablet A.
18) Find the apparent absorption rate constant (ka) of remoxipride given as Tablet A.
19) Find the peak time of Tablet A.
20) Find the single dose Cpmax for tablet A (mg/L)
21) Find the mean dissolution time (MDT) of Tablet A, the brand name product (hr).
22) Is Tablet B, the generic product is bioequivalent to Tablet A. Why or why not?
23) Find N for BID dosing.
24) Find Cpss max for two caps bid for the brand name product.
25) Find Cpss avg for two caps bid for the brand name product.
26) Find Cpss min for two caps bid for the brand name product.
27) Which change in physiological status would result in the most significant change in
the TBC of remoxipride?
a) Changes which effect the flow of blood to the liver.
b) Changes which effect the flow of blood to the kidney.
c) Changes which effect the function of the liver.

d) Changes which effect the function of the kidney.

Your patient is experiencing that change. That physiological function was up 75% above
normal (F = 1.75).
28) Find his new renal clearance
29) Find his new hepatic clearance.
30) Find his new total body clearance.
31) Assuming now change in volume of distribution, find his new half life.
32 Assuming no change in dosage regimen, find his new N.
33 What dosing regimen would you recommend to return his plasma concentrations back
to normal (within 110% of max and 90% of min)?

15.7.2 REMOXIPRIDE SOLUTIONS

1. MRT = 6.93hr
–1
2. k e = 0.144hr
3. Cp 0 = 0.88mg ⁄ L
4. Vd = 50L
5. T1 ⁄ 2 = 4.8hr
6. Cl = 7.28L ⁄ hr
7. Cl r = 1.8L ⁄ hr
8. Cl h = 5.46L ⁄ hr
9. Er = 0.025
10. Eh = 0.06
11. Oral solution MRT = 8hr
12. Oral solution MAT = 1.07hr

–1
13. Oral solution Ka = 0.935hr
14. Oral solution bioavailability f = 0.95
15. Oral solution peak time 2.4hr
16. Tablet A MRT = 8.5hr
17. Tablet A MAT = 1.57hr

–1
18. Tablet A Ka = 0.637hr
19. Tablet A peak time 3.0hr
20. Tablet A single dose Cp max = 1.03mg ⁄ L
21. Tablet A MDT = 0.5hr
22. Tablet B is not bioequivalent to Tablet A because peak time and Cp max are out of
federal guidelines.
23. For dosing BID, N = 2.5

ss
24. Cp max = 3.88mg ⁄ L
ss
25. Cp avg = 1.85mg ⁄ L
ss
26. Cp min = 0.685mg ⁄ L
27. The change in physiological status that would result in the most significant change
in TBC of remoxipride is (C) - changes
which effect the function of the liver.
28. New renal clearance = no change
29. New Cl h = 9.0L ⁄ hr
30. New Cl s = 10.8L ⁄ hr
31. New T1 ⁄ 2 = 3.2hr
32. New N = 3.75

33. The dosing regimen to recommend = 200 mg TID

15.8 Naproxen
Naprosyn@ (naproxen) is a nonsteroidal anti-inflammatory drug (NSAID) with
analgesic properties. It is well absorbed (f = 0.95) and highly protein bound (98%)
with a volume of distribution of about 10 L and a half-life of 13 hours in normal
adults. It is almost entirely cleared by hepatic function (CLr = 1%) with about one-
third being metabolized to the 6-o-desmethylnaproxen (which is further metabo-
lized by conjugation) and two-thirds being conjugated directly. Both the 6-o-des-
methyl metabolites as well as the conjugates are inactive.
Normal dosing is 500 mg Naproxen BID. You stock 200 and 500 mg tablets in
your HMO.
For the following conditions, new parameters are given in parentheses.
Concomitant treatment with Probenecid, a uricosuric which increases the urinary

excretion of uric acid, while not interfering with the protein binding, effectively
blocks the hepatic conjugation process reducing the hepatic function (Clinth ) to
one-third of normal.
In chronic renal failure (Fir = 0.1) the protein binding is reduced (94%) because of
uremia. This results in a marginal increase in half-life (14 hr.)
In rheumatoid arthritis, hypoalbuminaemia results in a reduction in protein binding

(97%) and increase in the volume of distribution (13 L).
Elderly patients exhibit a decrease in binding (96%), but no change in half-life or

volume of distribution.
For each of the conditions, (with Probenecid, chronic renal failure, arthritic, and
elderly), please recommend a dosage regimen which would give approximately the
same plasma concentrations of free naproxen obtained in the normal case (+ 10%.)
Constants:
L - renal blood perfusion ⋅ 70kg ⋅ 60min
Q r = 0.0191 ------------------- L
--------- ≈ 80 -----blood
min ⋅ kg hr hr
L min L
Q H = 0.0238 -------------------- hepatic blood perfusion ⋅ 70kg ⋅ 60--------- ≈ 100 -----blood
min ⋅ kg hr hr
Extraction ratios are calculated for normals and considered to be constant through-
out.

15.8.1 NAPROXEN QUESTIONS

TABLE 1-1. Question Numbers For Exam
Patient Condition Normal Probenecid Chronic Rheumatoid Elderly
treatment Renal Failure arthritis
Dose(mg) 1 27 51 75 99
f 2 28 52 76 100
fu 3 29 53 77 101
Vd (L) 4 30 54 78 102
k (hr-1) 5 31 55 79 103
T 1/2 (hr) 6 32 56 80 104
AUC (mg/L*hr) 7 33 57 81 105
% Cl h 8 34 58 82 106
% Cl r 9 35 59 83 107
Cl tot (L/hr) 10 36 60 84 108
Cl h (L/hr) 11 37 61 85 109
Cl r (L/hr) 12 38 62 86 110
Eh 13
Er 14
Cl h (L/hr) 15 39 63 87 111
int
Cl r (L/hr) 16 40 64 88 112
int
FR h 17 41 65 89 113
FI h 18 42 66 90 114
FR r 19 43 67 91 115
FI r 20 44 68 92 116
FCL 21 45 69 93 117
τ (hr) 22 46 70 94 118
N 23 47 71 95 119
ss µg  24 48 72 96 120
Cp  -------
-
max free  mL

ss  µg  25 49 73 97 121
Cp --------
avg free  mL
ss µg  26 50 74 98 122
Cp  -------
-
min free  mL
Answer Pool
S M L XL XXL XXXL
A 0.000067 0.0182 0.100 1.0 10.0 100
B 0.0005 0.0200 0.133 1.1 11.3 200
C 0.0050 0.0300 0.177 1.4 12.0 303
D 0.0080 0.0400 0.182 1.5 13.0 356
E 0.0089 0.0495 0.267 1.6 13.3 500
F 0.0092 0.0533 0.315 1.7 14.0 595
G 0.0095 0.0600 0.333 1.8 26.5 891
H 0.0097 0.0610 0.341 1.9 31.7 1044
I 0.0098 0.0675 0.528 2.0 38.1 2000
J 0.0099 0.0700 0.533 2.1 45.0 3000
A 0.0790 0.577 2.2 50.0
B 0.0798 0.615 2.9 53.0
C 0.0857 0.675 3.0 62.0
D 0.0923 0.700 5.3 80.0
E 0.0950 0.790 6.2 86.0
F 0.0970 0.798 8.0 92.0
G 0.0990 0.857 8.5 97.0
I 0.0999 0.923 9.0 99.0
J 0.09997 0.95 9.9 99.97

15.8.2 NAPROXEN SOLUTIONS

TABLE 1-1. Question Numbers For Exam
Patient Condition Normal Probenecid Chronic Rheumatoid Elderly
treatment Renal Failure arthritis
Dose(mg) 1. 500 mg 27. 200 51. 500 75. 500 99. 200
f 2. 0.95 28. 0.95 52. 0.95 76. 0.95 100. 0.95
fu 3. 0.02 29. 0.02 53. 0.06 77. 0.03 101. 0.04
Vd (L) 4. 10 30. 10 54. 31.67 78. 13 102. 10
k (hr-1) 5. 0.0533 31. 0.0182 55. 0.0495 79. 0.061 103. 0.533
T 1/2 (hr) 6. 13 32. 38.1 56. 14 80. 11.3 104. 13
AUC (mg/L*hr) 7. 891 33. 1044 57. 303 81. 595 105. 356
% Cl h 8. 99 34. 97 58. 99.97 82. 99 106. 99
% Cl r 9. 1 35. 3 59. 0.03 83. 1 107. 1
Cl tot (L/hr) 10. 0.533 36. 0.182 60. 1.57 84. 0.798 108. 0.533
Cl h (L/hr) 11. 0.528 37. 0.177 61. 1.57 85. 0.790 109. 0.528
Cl r (L/hr) 12. 0.005 38. 0.005 62. 0.005 86. 0.008 110. 0.005
Eh 13. 0.005
Er 14. 0.000067
Cl h (L/hr) 15. 26.5 39. 8.84 63. 26.5 87. 26.5 111. 13.26
int
Cl r (L/hr) 16. 0.267 40. 0.267 64. 0.00889 88. 0.267 112. 0.133
int
FR h 17. 1 41. 1 65. 1 89. 1 113. 1
FI h 18. 1 42. 0.333 66. 3 90. 1.5 114. 1
FR r 19. 1 43. 1 67. 1 91. 1 115. 1
FI r 20. 1 44. 1 68. 0.1 92. 1.5 116. 1
FCL 21. 1 45. 0.341 69. 2.94 93. 1.5 117. 1
τ (hr) 22. 12 46. 12 70. 12 94. 12 118. 8

N 23. 0.923 47. 0.315 71. 0.857 95. 1.06 119. 0.615
ss µg- 24. 2.01 48. 1.94 72. 2.01 96. 2.1 120. 2.2
Cp  -------
max free  mL
ss µg- 25. 1.5 49. 1.74 73. 1.5 97. 1.5 121. 1.78
Cp  -------
avg free  mL
ss µg  26. 1.06 50. 1.55 74. 1.1 98. 1.01 122. 1.42
Cp  -------
-
min free  mL

15.8.3
1. Dose = 500 mg (given)
2. Bioavailability (f) = 0.95 (given)
3. Unbound Fraction = 0.02 (given)
4. V d = 10L (given)
0.693 –1
5. k = ------------- = 0.0533hr
t1 ⁄ 2
6. t 1 ⁄ 2 = 13hr (given)
f ⋅ Dose
7. AUC = ------------------- = 891L
k ⋅ Vd
8. %Cl h = 100 – %Cl r = 99
9. %Cl r = 1 (given)
10. Cl tot = k ⋅ V d = 0.533L ⁄ hr
11. Cl h = Cl tot ⋅ %Cl h = 0.528L ⁄ hr
12. Cl r = Cl tot ⋅ %Cl r = 0.005L ⁄ hr
Cl
13. E h = -------h- = 0.00528
Qh
Cl
14. E r = --------r = 0.000067
Qr
Q ⋅ Cl h
------------------
Q – Cl
15. Cl h = ------------------h- = 26.5L ⁄ hr
int
fu
Q ⋅ Cl
-----------------r-
Q – Cl
16. Cl r = ------------------r = 0.267L ⁄ hr
int
fu
17. FR h = 1 (given)
18. FI h = 1 (given)

19. FR r = 1 (given)
20. FI r = 1 (given)
21. F Cl = 1 (given)
22. τ = 12hr (given)
τ
23. N = --------- = 0.923
t1 ⁄ 2
ss fu ⋅ S ⋅ f ⋅ D 1 µg-
24. Cp = -------------------------- ⋅ -------------------- = 2.0 -------
N
1 –  ---
max free V 1 mL
2
ss f u ⋅ S ⋅ f ⋅ D fu ⋅ S ⋅ f ⋅ D µg-
25. Cp = -------------------------- = ------------------------------ = 1.5 -------
avg free V⋅K⋅τ V ⋅ 0.693 ⋅ N mL
N
 1---
ss fu ⋅ S ⋅ f ⋅ D  2 µg-
26. Cp = -------------------------- ⋅ -------------------- = 1.1 -------
N
1 –  1---
min free V mL
2
27. Dose = mg
28. Bioavailability (f) = 0.95 (no change)
29. Unbound Fraction = 0.02 (no change - given)
30. V d = 10L (given)
0.693
31. k = ------------- = 0.0533hr
–1
t1 ⁄ 2
32. t 1 ⁄ 2 = 13hr (given)
f ⋅ Dose
33. AUC = ------------------- = 891L
k ⋅ Vd
34. %Cl h = 100 – %Cl r = 99
35. %Cl r = 1 (given)
36. Cl tot = k ⋅ V d = 0.533L ⁄ hr
37. Cl h = Cl tot ⋅ %Cl h = 0.528L ⁄ hr

38. Cl r = Cl tot ⋅ %Cl r = 0.005L ⁄ hr
Q ⋅ Cl h
------------------
Q – Cl
39. Cl h = ------------------h- = 26.5L ⁄ hr
int
fu
Q ⋅ Cl
-----------------r-
Q – Cl
40. Cl r = ------------------r = 0.267L ⁄ hr
int
fu
τ
47. N = --------- = 0.923
t1 ⁄ 2
ss fu ⋅ S ⋅ f ⋅ D 1 µg-
48. Cp = -------------------------- ⋅ -------------------- = 2.0 -------
N
1 –  1---
max free V mL
2
ss f u ⋅ S ⋅ f ⋅ D fu ⋅ S ⋅ f ⋅ D µg-
49. Cp = -------------------------- = ------------------------------ = 1.5 -------
N
 1---
ss fu ⋅ S ⋅ f ⋅ D  2 µg-
50. Cp = -------------------------- ⋅ -------------------- = 1.1 -------
N
1 –  1---
min free V mL
2
51. Dose = mg
54. V d = 10L (given)

0.693 –1
55. k = ------------- = 0.0533hr
t1 ⁄ 2
56. t 1 ⁄ 2 = 13hr (given)
f ⋅ Dose
57. AUC = ------------------- = 891L
k ⋅ Vd
58. %Cl h = 100 – %Cl r = 99
59. %Cl r = 1 (given)
60. Cl tot = k ⋅ V d = 0.533L ⁄ hr
61. Cl h = Cl tot ⋅ %Cl h = 0.528L ⁄ hr
62. Cl r = Cl tot ⋅ %Cl r = 0.005L ⁄ hr
Q ⋅ Cl h
------------------
Q – Cl
63. Cl h = ------------------h- = 26.5L ⁄ hr
int fu
Q ⋅ Cl
-----------------r-
Q – Cl
64. Cl r = ------------------r = 0.267L ⁄ hr
int fu
τ
71. N = --------- = 0.923
t1 ⁄ 2
ss fu ⋅ S ⋅ f ⋅ D 1 µg-
72. Cp = -------------------------- ⋅ -------------------- = 2.0 -------
1 –  1---
max free V N mL
2

ss f u ⋅ S ⋅ f ⋅ D fu ⋅ S ⋅ f ⋅ D µg-
73. Cp = -------------------------- = ------------------------------ = 1.5 -------
 1--- N
ss fu ⋅ S ⋅ f ⋅ D  2 µg-
74. Cp = -------------------------- ⋅ -------------------- = 1.1 -------
1 –  1---
min free V N mL
2
75. Dose = mg
78. V d = 10L (given)
0.693 –1
79. k = ------------- = 0.0533hr
t1 ⁄ 2
80. t 1 ⁄ 2 = 13hr (given)
f ⋅ Dose
81. AUC = ------------------- = 891L
k ⋅ Vd
82. %Cl h = 100 – %Cl r = 99
83. %Cl r = 1 (given)
84. Cl tot = k ⋅ V d = 0.533L ⁄ hr
85. Cl h = Cl tot ⋅ %Cl h = 0.528L ⁄ hr
86. Cl r = Cl tot ⋅ %Cl r = 0.005L ⁄ hr
Q ⋅ Cl h
------------------
Q – Cl
87. Cl h = ------------------h- = 26.5L ⁄ hr
int fu
Q ⋅ Cl
-----------------r-
Q – Cl
88. Cl r = ------------------r = 0.267L ⁄ hr
int fu

τ
95. N = --------- = 0.923
t1 ⁄ 2
ss fu ⋅ S ⋅ f ⋅ D 1 µg-
96. Cp = -------------------------- ⋅ -------------------- = 2.0 -------
N
1 –  ---
max free V 1 mL
2
ss f u ⋅ S ⋅ f ⋅ D fu ⋅ S ⋅ f ⋅ D µg-
97. Cp = -------------------------- = ------------------------------ = 1.5 -------
N
 1---
ss fu ⋅ S ⋅ f ⋅ D  2 µg-
98. Cp = -------------------------- ⋅ -------------------- = 1.1 -------
N
1 –  1---
min free V mL
2
99. Dose = mg
102. V d = 10L (given)
0.693 –1
103. k = ------------- = 0.0533hr
t1 ⁄ 2
104. t1 ⁄ 2 = 13hr (given)
f ⋅ Dose
105. AUC = ------------------- = 891L
k ⋅ Vd
106. %Cl h = 100 – %Cl r = 99
107. %Cl r = 1 (given)
108. Cl tot = k ⋅ V d = 0.533L ⁄ hr
109. Cl h = Cl tot ⋅ %Cl h = 0.528L ⁄ hr

110. Cl r = Cl tot ⋅ %Cl r = 0.005L ⁄ hr
Q ⋅ Cl h
------------------
Q – Cl
111. Cl h = ------------------h- = 26.5L ⁄ hr
int
fu
Q ⋅ Cl
-----------------r-
Q – Cl
112. Cl r = ------------------r = 0.267L ⁄ hr
int
fu
113. FR h = 1 (given)
114. FI h = 1 (given)
115. FR r = 1 (given)
116. FI r = 1 (given)
117. F Cl = 1 (given)
118. τ = 12hr (given)
τ
119. N = --------- = 0.923
t1 ⁄ 2
ss fu ⋅ S ⋅ f ⋅ D 1 µg-
120. Cp = -------------------------- ⋅ -------------------- = 2.0 -------
N
1 –  1---
max free V mL
2
ss fu ⋅ S ⋅ f ⋅ D f u ⋅ S ⋅ f ⋅ D µg-
121. Cp = -------------------------- = ------------------------------ = 1.5 -------
N
 1---
ss fu ⋅ S ⋅ f ⋅ D  2 µg-
122. Cp = -------------------------- ⋅ -------------------- = 1.1 -------
N
1 –  1---
min free V mL
2

CHAPTER 16 Exam 3
Author:
Reviewer:

Exam 3
16.1 Pharmacokinetics Final Exam

Summer 1996
Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) with antidepressant properties. After oral
administration, the drug is almost completely absorbed from the gastrointestinal tract, however despite complete
absorption, oral bioavailibiliity in man is approximately 50% on account of first-pass hepatic metabolism. Steady-state
plasma concentrations are achieved within 5 to 10 days after initiation of therapy and are 30 to 50 % higher than those
predicted from single dose data. Fluvoxamine displays non-linear steady state pharmacokinetics over the therapeutic
dose range, with disproportionally higher plasma concentrations with higher dosages. Plasma protein binding of flu-
voxamine (77%) is low compared with that of other SSRI’s.
V.L. is a 39 year old, 110# female suffering from severe depression. She was admitted to the hospital and pre-
scribed 100mg BID of Fluvoxamine but still her depression was uncontrolled at this dose. Her plasma concentration
on this regimen was 20ug/L. After her physician increased her dose to 300 mg BID her plasma concentration was 500
ug/L. V.L.’s depression was controlled at this dose, however she was complaining of adverse effects. The therapeutic
range (total drug ug/L) of fluvoxamine is 20-500. Fluvoxamine is metabolized extensively (93%) by the liver to an
inactive metabolite.
1. What was her clearance on the 100 mg BID regimen (L/day)?
2. What was her clearance on the 300 mg BID regimen (L/day)?
3. What was her V max (mg/day)?
4. What was her K m (mg/L)?
5. The doctor would like to change her therapy in order to minimize side effects. What dose would you
recommend tolower her plasma concentration to 300 ug/L?
V.L. has major complications from a combined hepatitis B infection and cirrhosis of the liver. As a result her
protein binding is reduced to 66%, her K m changes to 0.03 mg/L and her V max changes to 100mg/day.
6. What would be her plasma concentration of total fluvoxamine if she maintained the regimen from
question 5 (mg/L)?
7. What is her free plasma concentation (mg/L)?
8. What total fluvoxamine plasma concentration would you recommend achieving to get her free fluvoxa-
mine plasma concentration back to that of the regimen in question 5 (mg/L)?

Exam 3
9. What daily dose of fluvoxamine (by I.V. bolus) would you recommend to get her average free fluvoxamine
plasma concentration approximately back to what it was when she was healthy (mg/day)?
Flurbiprofen is a nonsteroidal anti-inflammatory drug (NSAID) which is a potent inhibitor of prostaglandin
synthesis. It was introduced in the U.S. in 1986 for the treatment of osteoarthritis, rheumatoid arthritis, acute gouty
arthritis, and ankylosing spondylitis. Flurbiprofen is stereoselectively and extensively bound to plasma albumin.
Approximately 99% of the drug is metabolized by the liver, with trace amounts excreted in the urine as unchanged
drug. Flurbiprofen is 80% bioavailable. The recommended dosages for flurbiprofen are 50 mg q 4-6 hr as needed for
analgesia and 100-300 mg/day for the treatment of inflammatory conditions.
The following healthy and sick parameters are given for the patient V.L., 110# suffering from severe arthritis.
Her effective hepatic blood flow is 24 mL/min/kg and effective renal blood flow is 15.0 mL/min/kg. Her healthy half-
life is 6 hours. Dr. M. recommends 100 mg flurbiprofen BID.
Healthy Sick
Vd 0.15 L/kg 0.19L/kg
% Bound Drug 99.0% 97.0%
10. What is her total body clearance of flurbiprofen (L/hr)?

11. What is the intrinsic hepatic clearance (L/hr)?
12. What is the hepatic extraction ratio?
ss
13. What is the Cp max of total flurbiprofen in mg/L?
ss
14. What is the Cp min of total flurbiprofen in mg/L?
ss
15. What is the Cp max of free flurbiprofen in mic/L?
ss
16. What is the Cp min of free flurbiprofen in mic/L?
17. V.L. is now suffering from chronic renal insufficiency. Bound flurbiprofen has now decreased to 97%
due to significant uremia. What is her new hepatic clearance (L/hr)?
18. What is her new k?
19. What is the new N?
20. What would her dose be now, if you wanted to maintain approximately the same free plasma concentra-
tions as the previous therapy with the largest tau?
21. The renal insufficiency clears up and she comes down with mono. Her plasma albumin drops to 50% of
normal thus reducing the bound fraction to 96%. What is her new hepatic clearance using the healthy V d ?
22. What would her dose be now, if you wanted to maintain approximately the same plasma concentrations as
the previous therapy with the largest tau?

Exam 3
23. The mono clears up, but now there seems to be hepatic stenosis. Her plasma flow is reduced to 50% of
normal. What would her dose be now, if you wanted to maintain approximately the same concentrations
as the previous therapy with the largest tau?
Clentiazem is a chlorinated analog of diltiazem. It is currently undergoing clinical evaluation for the treatment
of angina pectoris and hypertension. The primary mechanism responsible for the antihypertensive effect of CLZ is a
decrease in peripheral vascular resistance due to the blockade of calcium channels. The following information was
obtained from a dose of 20 mg Clentiazem given I.V.
Table 2:
A1 37.52ng ⁄ mL
α 2.70hr
–1
B1 16.17ng ⁄ mL
β 0.078hr
–1
k 10 –1
0.243hr
k 12 –1
1.67hr
k 21 –1
0.868hr
AUMC 2
2729.6ng ⁄ mL ⁄ hr
24. Can this data be adequately evaluated by a one compartment model?
25. What is the volume of the central compartment (L)?
26. What is the clearance of clentiazem (L/hr)?
27. What is the MRT of clentiazem (hr)?
28. What is the Vd eff of clentiazem (L)?
29. What is the V β for clentiazem (L)?
30. What percent of the clentiazem dose is in the central compartment at equilibrium?

Exam 3
ss
31. What is the Cp max , and for a 20 mg IV daily dose clentiazem (ng/mL)?
ss
32. What is the Cp min for the above dosing regimen (ng/mL)?
ss
33. What is the Cp avg for the above dosing regimen (ng/mL)?
Any number from the answer pool may be used once, more than once, or not at all.
TABLE 2-1 Answer Pool
A
B
C
D
E
F
G
H
I
J
A
B
C
D
E
F
G
H
I
J

::
Tolbutamide (Problem 1)
Miners J, Foenander T, Wanwimolruk S, Gallus A, Birkett D. (European Journal of Clinical Pharmacology) The effect of sulphin-
pyrazone on oxidative drug metabolism in man: inhibition of tolbutamide elimination (1982) 22: 321-326.
About the drug: Tolbutamide is a sulfonylurea which has been used as an oral hypoglycemic agent in non-
insulin-dependent Diabetes Miletus with adult onset. In a study using normal, healthy, 70 kg volunteers the
following pharmacokinetic data was obtained. Tolbutamide is well absorbed. It is highly protein bound
(96%). The volume of distribution is 0.143 L/kg with a half-life of 6.93 hours in normal adults. Tolbutamide
is cleared entirely by hepatic function. Dosing: Tolbutamide (Orinase-brand name) is manufactured by
Upjohn. Both 250 and 500 mg tablets are manufactured. Both tablet sizes are available for prescription use.
The normal daily dose should not exceed 3 grams. Your consult should contain both an aggressive and
conservative dosage regimen recommendations when appropriate as well as calculations where appro-
priate.
Extraction ratios are calculated for normal individuals and are considered to be constant.
Qr = 0.0191 L/min/kg, Qh = 0.0238 L/min/kg.
Bioequivalence: In a study presented to you (Int J Clin Pharmacol Ther 1997 Jan; 35(1):43-6) A 500 mg
brand name tablet yielded an AUC of 499 mg/L *hr while a 500 mg generic tablet yielded an AUC of 498
mg/L *hr . The Cpmaxs were 55.1 vs 58.8 mic/mL and the Tmaxs were 4.55 vs 3.82 hr respectively. The
generic comes in 250 and 500 mg scored tablets and cost approximately 1/3 of the brand name. You have
been asked to prepare a recommendation for the P & T Committee for inclusion into the formulary for the
HMO. Please give your recommendation and support it with appropriate documentation.
(Short paragraph)
(Important variables and constants)
(Use other side for supportive documentation - appropriate calculations)

::
Elderly: Tolbutamide is mainly used for the treatment of middle aged and elderly patients. It is well docu-
mented that plasma albumen levels decrease with increasing age. This produces a net decrease in protein
binding equivalent to 92%, with no change in drug half-life or volume of distribution. Please prepare an ini-
tial consult for KT a 75 y/o, 70 kg, healthy male. Your consult should contain both an aggressive and conser-
vative dosage regimen recommendation which attempts to attain the free tolbutamide concentration range of
normal, healthy volunteers who were dosed at 250 mg TID as well as a short explanation of the observations.
(Short paragraph)

::
Concomitant treatment: Sulphinpyrazone, a drug used as an antithrombotic agent and inhibitor of platelet
aggregation has a potent side effect as a uricosuric agent. The uricosuric side effect increases the urinary
excretion of uric acid effectively blocking hepatic conjugation. Tests show that Sulphinpyrazone’s effect on
Tolbutamide is a reduction of liver function (Clinth*/Clinth = 0.6) to 60% of normal without interfering with
protein binding. Please prepare a dosage regimen consult for LM, an otherwise normal, 90 kg adult who was
maintained on 250 mg Orinase QID prior to taking this new drug as well as a short explanation of the obser-
vations.
(Short paragraph)

::
Systemic Alkalosis: Gastric acid loss caused by vomiting is a concern for the hypoglycemic patient using
Tolbutamide. Tolbutamide’s molecular structure contains an active sulfonamide group which ionizes at
increased plasma pH levels associated with metabolic alkalosis from gastric acid loss in vomition. Because of
this ionization Tolbutamide protein binding to alpha1-acid glycoprotein is increased to 98%, with a decrease
in volume of distribution to 6.375 L. Please prepare a dosage regimen consult for AM, an otherwise normal,
80 kg adult who was maintained on 250 mg Orinase TID prior to this problem as well as a short explanation
of the observations. .
(Short paragraph)

::
Viral Hepatitis: Viral hepatitis causes a 72.5% increase in volume of distribution while and decreasing the
protein binding to 92% and the hepatic function by 25% (Clinth*/Clinth = 0.75). Please prepare a dosage reg-
imen consult for BE, an otherwise normal, 55 kg adult who was maintained on 250 mg Orinase BID prior to
this problem as well as a short explanation of the observations..
(Short paragraph)

::
161) Are the tablets bioequivalent? Why/ Why not?
Patient Normal Elderly Concomitant Systemic Viral Hepati-

Condition Treatment Alkylosis tis
Dose(mg) 500 mg 500 mg 500 mg 72) ??? mg tablet 92) ??? mg 115) ??? mg 138)??? mg
IV Brand tablet Generic tablet tablet tablet tablet
f 1) 22) 49) 73) 93) 116) 139)
fu 2) 23) 50) 74) 94) 117) 140)
Vd (L) 3) 24) 51) 75) 95) 118) 141)
k (hr-1) 4) 25) 52) 76) 96) 119) 142)
T 1/2 (hr) 5) 26) 53) 77) 97) 120) 143)

AUC (mg/L*hr) 6) 27) 54) 78) 98) 121) 144)
2) 7) 28) 55)
AUMC (mg/L*hr
MRT 8) 29) 56)
MAT 30) 57)
Ka 31) 58)
Peak Time 9) 32) 59)
Cl tot (L/hr) 10) 33) 60) 79) 99) 122) 145)
Cl h (L/hr) 11) 34) 61) 80) 100) 123) 146)
Cl r (L/hr) 12) 35) 62) 81) 101) 124) 147)
Eh 13) 36) 63) 82) 102 125) 148)
Er 14) 37) 64) 83) 103) 126) 149)
Cl h (L/hr) 15) 38) 65) 84) 104) 127) 150)

int
Cl r (L/hr) 16) 39) 66) 85) 105) 128) 151)

int
FR h 17) 40) 67) 85) 106 129) 152)
FI h 18) 41) 68) 87) 107) 130) 153)
FR r 19) 42) 69) 73) 108) 131) 154)
FI r 20) 43) 70) 77) 109) 132) 155)
FCL 21) 44) 71) 81) 110) 133) 156)
τ (hr) 45) 85) 111) 134) 157)
N 46) 89) 112) 135) 158)

47) 90) 113) 136) 159)
ss µg-
 -------
Cp
max f ree  mL
48) 91) 114) 137) 160)

ss µg-
 -------
Cp
min free  mL


Basic Pharmacokinetics

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Basic Pharmacokinetics

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Basic Pharmacokinetics PHA 443

Course Content available @ http://pharmacy.creighton.edu

Schedule Spring 1999

April 12 7–8 Oral Dosing,

My vision - what I do.

Evolution of style - Where did it come from?

Student Centered, Active Learning Process

Objective: Describe (II) the role of objectives in evaluation process

Connect course objectives to desired outcomes

Course objectives for Bioavailability:

Connect course exams to course objectives.

The concept is reasonably straight forward:

1. tell them what you expect from them in detail,

My accountability to stick to the objectives.

Objective: Compare (III) various levels of expectations

Expectations for the course

Why might students fail?

I believe that there could be four reasons for failure:

Student is not intelligent or prepared enough to do his/her job.

Faculty refuses to do his/her job.

Student refuses to do his/her job.

Students experience problem outside their control.

Whose education is it anyway?

When students take responsibility, students win.

This is a competency based educational experience.

Objective: Describe (II) the process of initiation of group based learning

Establishing the Process

Objective: Describe (II) the responsibilities of the various players

Who are the Players?

Weekly Status Report

What does the facilitator do?

What do the QTLs do? Kizen.

Problem solving, not placing blame, is important.

What do the students do?

“You can observe a lot just by watching” Yogi Berra

Objective: Describe (II) the stages of group growth

Group Dynamics: Learning to work together.

2. Mental (Refer to Appendix E)

Student perceptions of group-based learning:

Does this process work?

Do the students think it works?

Passive Groups Active Groups

Passive Groups Active Groups

Some student perceptions:

Passive Groups Active Groups

Passive Groups Active Groups

GROUP:___________________ LEADER NAME:_____________________

DATE:__________________ LAB SECTION (circle one) A B

GROUP PROCESS - COMMENTS/CONCERNS/SUGGESTIONS:

COURSE CONTENT - COMMENTS/CONCERNS/SUGGESTIONS:

LIST PROBLEMS WORKED ON/CONCEPTS COVERED:

DID GROUP WORK OUTSIDE OF CLASS THIS WEEK:

MID-SEMESTER PEER/SELF GROUP INTERACTION ASSESSMENT

Assessment items Club Diamond Heart Spade extra

3. This person helps to redirect discussions/problem-solving when

5. This person exercises mutual respect for others in the group.

7. This person works well with the other group members.

8. This person does not monopolize group discussions.

9. This person is available outside of class for group work.

STRATEGY 3: Characterize the difficult people in your life

STRATEGY 4: Encourage people to change

STRATEGY 5: Know when to give up

Michael C. Makoid, Ph.D.

GROUP:_ LEADER NAME:___