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MODELS
SUBMITTED BY:
-DC/DT = VMAX . C / KM + C
KM = Michaelis constant
VMAX = Theoretical maximum
Rate of process
PLASMA DRUG CONCENTRATION TIME PROFILE
8
PHARMACOKINETIC PARAMETERS
i v bolus
i v bolus
Single oral Dose
i v infusion
Oral
Intermittent i v infusion drug
Multiple doses
PHARMACOKINETIC MODELS
Means of expressing mathematically or quantitatively, time course of drug
through out the body and compute meaningful pharmacokinetic parameters.
Useful in :
Characterize the behavior of drug in patient.
Predicting conc. Of drug in various body fluids with dosage regimen.
Calculating optimum dosage regimen for individual patient.
Evaluating bioequivalence between different formulation.
Explaining drug interaction.
Pharmacokinetic models are hypothetical structures that are used to describe the
fate of a drug in a biological system following its administration.
Model
Mathematical representation of the data.
It is just hypothetical
WHY MODEL THE DATA ?
There are three main reasons due to which the data is subjected to modelling.
1. Descriptive: to describe the drug kinetics in a simple way.
2. Predictive: to predict the time course of the drug after multiple dosing based
on single dose data, to predict the absorption profile of the drug from the iv
data.
3. Explanatory: to explain unclear observations.
PHARMACOKINETIC MODELING IS USEFUL IN :-
Prediction of drug concentration in plasma/ tissue/ urine at any point of time.
Determination of optimum dosage regimen for each patient.
Estimation of the possible accumulation of drugs/ metabolites.
Quantitative assessment of the effect of disease on drugs adme.
Correlation of drug concentration with pharmacological activity.
Evaluation of bioequivalence.
Understanding of d/i.
COMPARTMENTAL MODELS
A compartment is not a real physiological or anatomic region
but an imaginary or hypothetical one consisting of tissue/ group
of tissues with similar blood flow & affinity.
Our body is considered as composed of several compartments
connected reversibly with each other.
ADVANTAGES
1. Central compartment
Blood & highly perfused tissues such as heart, kidney, lungs, liver, etc.
2. Peripheral compartment
Poorly per fused tissues such as fat, bone, etc.
MODELS:
OPEN and CLOSED models:
The term open itself mean that, the administered drug dose is removed from
body by an excretory mechanism ( for most drugs, organs of excretion of drug is
kidney)
If the drug is not removed from the body then model refers as closed model.
LOADING DOSE
A drug dose does not show therapeutic activity unless it reaches the desired steady
state.
It takes about 4-5 half lives to attain it and therefore time taken will be too long if
the drug has a long half-life.
Plateau can be reached immediately by administering a dose that gives the desired
steady state instantaneously before the commencement of maintenance dose x0.
Such an initial or first dose intended to be therapeutic is called as priming dose or
loading dose x0,l.
CALCULATION OF LOADING DOSE
After e.V. Administration, cmax is always smaller than that achieved after i.V.
And hence loading dose is proportionally smaller.
For the drugs having a low therapeutic indices, the loading dose may be
divided into smaller doses to be given at a various intervals before the first
maintenance dose.
A simple equation for calculating loading dose is :
xo,l = css,av vd
F
CALCULATION.,
2. Rapid mixing
We also need to assume that the drug is mixed instantaneously in blood or
plasma.
3. Linear model
We will assume that drug elimination follows first order kinetics.
LINEAR MODEL - FIRST ORDER KINETICS
FIRST-ORDER KINETICS
MATHEMATICALLY
T1/2 = 0.693
KE (eq.8)
Elimination half life can be readily obtained from the graph of log c
versus t
Half life is a secondary parameter that depends upon the primary
parameters such as clearance and volume of distribution.
T1/2 = 0.693 V d
Cl T (eq.9)
APPARENT VOLUME OF DISTRIBUTION
Vd = xo/co
=I.V.Bolus dose/co (eq.11)
Example: 30 mg i.V. Bolus, plasma conc.= 0.732 mcg/ml.
Vol. Of dist. = 30mg/0.732mcg/ml =30000mcg/0.732mcg/ml
= 41 liter.
For drugs given as i.V.Bolus,
Vd (area)=xo/KE.Auc .12.A
For drugs admins. Extra. Vas.
Vd (area)=f xo/ke.Auc ..12.B
CLEARANCE
Clearance = rate of elimination
Plasma drug conc.. (Or) cl= dx /dt
C ., (eq.13)
Thus, renal clearance = rate of elimination by kidney
C
C
Total body clearance:
Clt = clr + clh + clother , (eq.14)
According to earlier definition
cl = dx /dt
C
Submitting eq.1 dx/dt = KE X , above eq. Becomes ,clt = KE X/ C .., (Eq 15)
By incorporating equation 1 and equation for vol. Of dist. ( Vd= X/C ) we can
get
clt =KE vd (eq.16)
Parallel equations can be written for renal and hepatic clearance.
Clh =km vd (eq.17)
Clr =ke vd (eq.18)
But, KE= 0.693/t1/2
So, clt = 0.693 vd (eq.19)
t1/2
For non compartmental method which follows one compartmental
kinetic is :
For drug given by i.V. Bolus
clt = xo ..20.A
Auc
For drug administered by e.V.
Clt = f xo ..20.B
Auc
For drug given by i.V. Bolus
renal clearance = xu .(eq. 21)
auc
ORGAN CLEARANCE
Rate of elimination by organ= rate of presentation to the organ rate of exit
from the organ.
Dx/dt =ro-kex eq 23
X=ro/ke(1-e-ket) eq 24
Since X =vdc
C= ro/kevd(1-e-ket) eq 25
= Ro/clt(1-e-ket) eq 26
At steady state. The rate of change of amount of drug in the body is zero ,eq
23 becomes
Zero=ro-kexss 27
Kexss=ro 28
Css=ro/kevd 29
=Ro/clt i.E infusion rate ....30
Clearance
Substituting eq. 30 in eq. 26
C=css(1-e-ket) 31
Rearrangement yields:
[Css-c]=e-ket . ...32
Css
Log CSS-C = -ket 33
Css 2.303
If n is the no. Of half lives passed since the start of infusion(t/t1/2)
Eq. Can be written as
C=CSS [1-(1/2)n] 34
INFUSION PLUS LOADING DOSE
XO,L=CSSVD 35
SUBSTITUTION OF CSS=RO/KEVD
XO,L=RO/KE 36
Drug at site
R0 Blood & other zero order elimination
Body tissues
Absorption
o Rate of drug absorption as in case of CDDS , is constant and continues until
the amount of drug at the absorption site (Ex. GIT) is depleted.
o All equations for plasma drug conc. Profile for constant rate i.V. Infusion
are also applicable to this model.
ONE COMPARTMENT MODEL: EXTRA VASCULAR
ADMIN ( FIRST ORDER ABSORPTION)
Drug that enters the body by first order absorption process gets distributed in
the body according to one compartment kinetic and is eliminated by first
order process.
The model can be depicted as follows and final equation is as follows
Ka KE
Drug at Blood & other elimination
site First order Body tissues
absorption
MULTI- COMPARTMENT
MODELS
Ideally a true pharmacokinetic model should be the one with a rate constant for
each tissue undergoing equilibrium.
Therefore best approach is to pool together tissues on the basis of similarity in
their distribution characteristics.
The drug disposition occurs by first order.
Multi-compartment characteristics are best described by administration as i.v
bolus and observing the manner in which the plasma concentration declines with
time.
The no. Of exponentials required to describe such a plasma level-time profile
determines the no. Of kinetically homogeneous compartments into which a
drug will distribute.
The simplest and commonest is the two compartment model which classifies the
body tissues in two categories :
1. Central compartment or compartment 1
2. Peripheral or tissue compartment or compartment 2.
TWO COMPARTMENT OPEN MODEL-IV BOLUS
ADMINISTRATION:
Elimination from central compartment
Fig:
1 2
Central peripheral
After the iv bolus of a drug the decline in the plasma conc. Is bi-exponential.
Two disposition processes- distribution and elimination.
These two processes are only evident when a semi log plot of C vs. T is
made.
Initially, the conc. Of drug in the central compartment declines rapidly, due
to the distribution of drug from the central compartment to the peripheral
compartment. This is called distributive phase.
Extending the relationship X= vd C
Dcc = K21 xp K12 xc KE xc
Dt vp vc vc
X= Amt. Of drug in the body at any time t remaining to be eliminated
C=drug conc in plasma
Vd =proportionality const app. Volume of distribution
Xc and xp=amt of drug in C1 and C2
Vc and vp=apparent volumes of C1 and C2
= K12 xc K21 xp
Vc vp On integration equation gives conc of drug in central and
peripheral compartments at any given time t
Cp = xo [( ) (K b)e ]
K21 a e-at + 12
-bt
Vc ba ab
Xo = iv bolus dose
The relation between hybrid and microconstants is given as :
a + b = K12 + K21 + KE
A b = K21 KE
Cc = a e-at + be-bt
Cc=distribution exponent + elimination
exponent
A and B are hybrid constants for two exponents and can be resolved by graph
by method of residuals.
A = X0 [K21 - A] = CO [K21 A]
VC B A BA
B = X0 [K21 - B] = CO [K21 B]
VC AB AB
1 2
Central Peripheral
The plasma or central compartment conc of a drug when administered as constant rate (0 order) i.V. Infusion is
given as:
VC KE ba a-b
At steady state (i.E.At time infinity) the second and the third term in the bracket becomes zero and the equation
reduces to:
Css = R0
Vc ke
Now VC KE = vd b
Css = r0 = r0
Vdb clt
Ke
TWO-COMPARTMENT OPEN MODEL-EXTRAVASCULAR
ADMINISTRATION
First - order absorption :
For a drug that enters the body by a first-order absorption process and
distributed according to two compartment model, the rate of change in drug
conc in the central compartment is described by three exponents :
An absorption exponent, and the two usual exponents that describe drug
disposition.
The plasma conc at any time t is
C = n e-kat + l e-at + m e-bt
C = absorption + distribution + elimination
Exponent exponent exponent
Besides the method of residuals, ka can also be found by loo-riegelman method
for drug that follows two-compartment characteristics.
Despite its complexity, the method can be applied to drugs that distribute in any
number of compartments.
CALCULATING Ka using Wagner-nelson
method(Bioavailability parameters)
WAGNER-NELSONS METHOD
THEORY: The working equations can be derived from the mass balance
equation: Gives the following eqaution with time and mass balance
ADVANTAGES:
The absorption and elimination processes can be quite similar and accurate determinations of
ka can still be made.
The absorption process doesn't have to be first order. This method can be used to investigate
the absorption process.
DISADVANTAGES:
The major disadvantage of this method is that you need to know the elimination rate constant,
from data collected following intravenous administration.
0
C= [e-KEt e-Kat] (1)
()
Log C = log A - (4)
2.303
Where ,
C = back extrapolated plasma concentration values
70
Plasma conc.-Time profile after oral administration of a single dose of a drug
Subtraction of true plasma concentration values i.e. equation
(2) from the extrapolated plasma concentration values i.e.
equation (3) yields a series of residual concentration value
C.
(C - C) = C = A e-Kat(5)
log C= log A - (6)
2.303
A plot of log C versus t yields a straight line with slope -Ka
/2.303 and y-intercept log A.
DEEP
CENTRAL TISSUE TISSUE
COMPARTMENT COMPARTMENT COMPARTMENT
K10
THREE COMPARTMENT CATENARY MODEL
RAPID IV
DRUG INPUT
K21 K13
DEEP
TISSUE CENTRAL
TISSUE
COMPARTMENT COMPARTMENT
COMPARTMENT
K31
K12
DRUG OUTPUT K10
When the drug is administered by i.V the drug will rapidly distributed in c.C
,less rapidly in to t.C. Very slowly in to deep tissue compartment.
Plasma profile
When the drug is administered by i.V the plasma conc. Will increased in c.C
this is first order release.
The conc. Of drug in c.C. Exhibits an initial distribution this is very rapid.
Drug in central compartment exhibits an initial distribution this is very rapid .
Pharmacokinetic parameters
Bioloigical half-life ::
It is defined as the time taken for the amount of drug in the body as well as
plasma to decline by one half or 50% its initial value.
Concentration of drug in plasma as a function of time is
c=a e - t+ b e - t+ c e - t
In this equation >> some time after the distributive phase (i.e. When time
become large) the two right hand side terms values are equal to zero.
The eq.. Is converted in to
c=a e-t
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REFERENCES :
BIOPHARMACEUTICS AND PHARMACOKINETICS.
P L MEDAN, 1ST EDN
BIOPHARMACEUTICS AND PHARMACOKINETICS.
D.M BRAHMANKAR AND SUNIL. B .JAISWAL, 1ST EDN
APPLIED BIOPHARMACEUTICS AND PHARMACOKINETICS
LEON SHARGEL AND ANDREW YU,
4TH EDN.
BIOPHARMACEUTICS AND CLINICAL PHARMACOKINETICS BY MILO
GIBALDI, 4TH EDN.
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