DOSE-EFFECT RELATIONSHIP

The intensity and duration of a drugs

effects are a function of the drug dose and
drug concentration at the effect site

Monitoring Dose-Effect
Level
Molecular (e.g, enzyme inhibition)
Cellular (in vitro tissue culture, blood cells)
Tissue or organ (in vitro or in vivo)
Organism
Endpoint used to measure effect may be
different at each level
Overall effect = sum of multiple drug effects
and physiological response to drug effects
Dose-Effect Endpoints
Graded
Quantal
Continuous scale (dose effect)
Measured in a single biologic unit
Relates dose to intensity of effect
All-or-none pharmacologic effect
Population studies
Relates dose to frequency of effect
0
5
10
15
20
25
0 100 200 300 400 500
Erythropoietin and Anemia
Erythropoietin Dose [units/kg]
Peak
Hematocrit
Increment
[%]
Eschbach et al. NEJM 316:73-8, 1987
Drug-Receptor Interactions
k
1

k
2

Drug
Receptor
Effect
Drug-Receptor
Complex
Effect =
Maximal effect [Drug]
K
D
+ [Drug]
(K
D
= k
2
/k
1
)
Ligand-binding
domain
Effector domain
Effect =
[Drug]
K
D
+ [Drug]
Maximal effect
[Drug]
K
D
+ [Drug]
Dose-Effect Relationship
Effect =
Maximal effect [Drug]
K
D
+ [Drug]
Effect = Maximal effect if [Dose] >> K
D
0
20
40
60
80
100
0 200 400 600 800
Graded Dose-Effect Curve
% of
Maximal
Effect
[Drug]
EC
50

Maximal effect
0
20
40
60
80
100
1 10 100 1000
Log Dose-Effect Curve
% of
Maximal
Effect
[Drug]
EC
50

0
1
2
3
4
5
6
7
0 1 2 3
Lidocaine Graded Dose-Effect
Lidocaine Blood Level [g/ml]
Analog
Pain Score
Ferrante et al. Anesth Analg 82:91-7, 1996
0
20
40
60
80
100
1 10 100 1000
Theophylline Dose-Effect
PDE Inhibition
Relaxation
% Control
Theophylline [M]
Rabe et al. Eur Respir J 8:637-42, 1995
Metformin Dose-Response
0
20
40
60
80
100
0
0.5
1
1.5
2
2.5
3
500 1000 1500 2000 2500
D
e
c
r
e
a
s
e

i
n

F
P
G

f
r
o
m

P
l
a
c
e
b
o

[
m
g
/
d
l
]

D
e
c
r
e
a
s
e

i
n

H
b
A
1
c

f
r
o
m

P
l
a
c
e
b
o

[
%
]

Dose [mg/d]
Garber et al. Am J Med 102:491-7, 1997
Dose-Effect Parameters
POTENCY:
EFFICACY:
The sensitivity of an organ or
tissue to the drug
The maximum effect
Comparing Dose-Effect Curves
0
20
40
60
80
100
1 10 100 1000
% of
Maximal
Effect
[Drug]
Drug A
Drug C
Drug B
Effect =
Maximal effect [Drug]
K
D
+ [Drug]
Thiopurine Cytotoxicity
0%
20%
40%
60%
80%
100%
10
-9
10
-8
10
-7
10
-6
10
-5
Cytotoxic
Effect
Thiopurine [M]
Thioguanine
Mercaptopurine
N
N
N
N
H
H
2
N
S
N
N
N
N
H
S
Adamson et al. Leukemia Res 18:805-10, 1994
Receptor-Mediated Effects
%
Maximum
Effect
[Drug]
Agonist
Antagonist
Partial agonist
100
80
60
40
20
0
1 100 10 1000
Drug Interactions
0
20
40
60
80
100
1 10 100 1000
% of
Maximal
Effect
[Drug]
Agonist
Agonist + competitive
antagonist
Agonist + non-competitive
antagonist
Graded Dose-Effect Analysis
Identify the therapeutic dose/concentration
Define site of drug action (receptor)
Classify effect produced by drug-receptor
interaction (agonist, antagonist)
Compare the relative potency and efficacy of
drugs that produce the same effect
Assess mechanism of drug interactions
Quantal Dose-Effect Distribution
Threshold Dose
# of
Subjects
0
10
20
30
40
50
1 3 5 7 9 11 13 15
ED
50

Cumulative Dose-Effect Curve
Dose
Cumulative
% of
Subjects
0
20
40
60
80
100
1 3 5 7 9 11 13 15
Cumulative Dose-Effect Study
Dose
Level
No. of
Subjects
No.
Respondin
g
%
Response
1 10 0 0
2 10 1 10
3 10 3 30
4 10 5 50
5 10 7 70
6 10 8 80
7 10 9 90
8 10 10 100
0
20
40
60
80
100
70 80 90100 200 300
Therapeutic and Toxic Effects
Dose
%
Responding
Therapeutic
Toxic
ED
99

TD
1

ED
50

TD
50

Indices
Doxorubicin Cardiotoxicity
Total Doxorubicin Dose [mg/m
2
]
Probability
of CHF
0
0.20
0.40
0.60
0.80
1.0
0 200 400 600 800 1000
von Hoff et al. Ann Intern Med 91:710-7, 1979
0
20
40
60
80
100
100 1000
Lidocaine Quantal Dose-Effect
%
Achieving
Complete
Analgesia
Total Lidocaine Dose (mg)
Ferrante et al. Anesth Analg 82:91-7, 1996
ED
50
= 400 mg
ED
90
= 490 mg
Antihypertensive Dose-Effect
Johnston Pharmacol Ther 55:53-93, 1992
Dose Range [mg] Lowest
Effective Dose
[mg] Drug Early Studies Present Dose
Propranolol 160-5000 160-320 80
Atenolol 100-2000 50-100 25
Hydrochlorthiazide 50-400 25-50 12.5
Captopril 75-1000 50-150 37.5
Methyldopa 500-6000 500-3000 750
Antihypertensive Drugs
0
20
40
60
80
100
Log Dose
% with
Maximal
Effect
Adverse
Effects
Desirable
Dose Range
Dose Range
most often used
Dose Intensity in Breast Cancer
0
20
40
60
80
100
0 0.2 0.4 0.6 0.8 1
Response
Rate (%)
Relative Dose Intensity
RDI
Hryniuk & Bush J Clin Oncol 2:1281, 1984
Doxorubicin Dose in Osteosarcoma
Dose Intensity (mg/m
2
/wk)
% with
>90%
Necrosis
Smith et al. JNCI 83:1460, 1993
0 100 200
0 5 10 15 20
0
20
40
60
80
100
Relating Dose to Effect In Vivo
Dose Effect
Effect site
Concentration
Pharmacokinetics Pharmacodynamics
Age
Absorption
Distribution
Elimination
Drug interactions
Tissue/organ sensitivity
(receptor status)
Effect Compartment (PK/PD Model)
k
0
k
1e
k
10
k
e0
Central Effect
Peripheral
k
12
k
21

dC
dt
=
k
0
V
c
(k
10
+ k
12
) -C +
k
21
- Xp
V
c

dX
p
dt
= k
12
- C-V
c
k
21
- X
p

dC
e
dt
=
k
1e
- C-V
c
V
e
k
e0
- C
e

E(t) =
E
max
-C
e
H
EC
50
H
+ C
e
H
Concentration and Effect vs. Time
0
2
4
6
8
10
0
20
40
60
80
100
0 5 10 15 20 25
Conc./
Amount
Effect
[% of E
max
]
Time
Central
Compartment
Peripheral
Compartment
Effect Compartment
Effect
Non-Steady State
Hysteresis and Proteresis Loops
0
1
2
3
4
0 1 2 3 4
0
1
2
3
4
0 1 2 3 4
Plasma Drug Concentration
Intensity of
Drug Effect
Intensity of
Drug Effect
Hysteresis Loop
(Counterclockwise)
Proteresis Loop
(Clockwise)
Equilibration delay in
plasma and effect site conc.
Formation of active
metabolite
Receptor up-regulation
Tolerance
Receptor tachyphylaxis
Role of Dose-Effect Studies
Drug development
Site of action
Selection of dose and schedule
Potency, efficacy and safety
Drug interactions
Patient management
Therapeutic drug monitoring
Risk-benefit (therapeutic indices)
THE END
Endpoints to Monitor Drug Effect
LEVEL ENDPOINT
Molecu
lar
Farnesyltransferase
inhibition
Cellula
r
Proliferation rate,
apoptosis
Tumor Response (change in
tumor size)
Organi
sm
Survival, quality of life
Farnesyltransferase Inhibitors for Cancer
Thiopurine Metabolic Activation
6
O
PO
4
CH
2
SH
N
N
N
N
OH HO
O
(PO
4
)
3
CH
2
SH
N
N
N
N
H
2
N
HO R
O
PO
4
CH
2
SH
N
N
N
N
OH HO
H
2
N
O
PO
4
CH
2
SH
N
N
N
N
OH HO
HO
MP TG
TIMP TGMP TXMP
(d)TGTP
6
PRPP PRPP
N
N
N
N
SH
H
2
N
H
N
N
N
N
SH
H
Therapeutic Indices
Therapeutic Ratio =
TD
50
ED
50
= 2.5
Certain Safety Factor =
TD
1
ED
99
= 1.3
Standard Safety Margin =
TD
1
- ED
99

ED
99
X 100 = 31%
Relative Dose Intensity
Dose Rate
mg/m
2
/wk
R.D.I.
Regimen Drugs Drugs
Regime
n
Cyclo 350 1
CAF-1 Doxo 15 1 1
FU 250 1
Cyclo 125 0.36
CAF-2 Doxo 12.5 0.83 0.56
FU 125 0.50
Oral Mercaptopurine
0
1
2
3
4
5
0 20 40 60 80 100
MP Dose (mg/m
2
)
MP AUC
[Mhr]
AUC =
Clearance
Dose F
Balis et al. Blood 92:3569-77, 1998
Pharmacodynamic Models
Fixed effect model
Linear model
Log-linear model
E
max
model
Sigmoid E
max
model
Effect = E
0
+ S[Drug]
Effect = I + SLog([Drug])
Effect =
EC
50
+ [Drug]
H

E
max
[Drug]
H

H
Sigmoid E
max
PD Model
0
20
40
60
80
100
0 20 40 60 80 100
0
20
40
60
80
100
1 10 100
[Drug]
Effect (%) Effect (%)
EC
50
EC
50

H = 0.1
H = 5
H = 2
H = 1
H = 0.5
Theophylline Pharmacodynamics
0
10
20
30
40
50
60
0 5 10 15 20 25 30
Theophylline [mg/L]
FEV
1

(% normal)
E
max
= 63%
EC
50
= 10 mg/L
Mitenko & Ogilvie NEJM 289:600-3, 1973
Carboplatin PK/PD
50
60
70
80
90
100
40 45 50 55 60 65 70 75
0
20
40
60
80
100
120
140
0 20 40 60 80 100 120 140
Carboplatin AUC
[ghr/ml]
Creatinine Clearance
[ml/min]
% Decrease
Platelet
Carboplatin
Cl
TB
[ml/min]
Van Echo et al. Semin Oncol 16:1-6, 1989
Carboplatin Adaptive Dosing
D[mg / m
2
] = 0.091 CL
CR
[ml / min/ m
2
]
prePlt trgtPlt
prePlt
100 priorRx
|
\

|
.
|
+ 86
D[mg] = trgtAUC[mg - min/ ml] (GFR[ml / min] + 25)
D[mg / m
2
] = trgtAUC[mg -min/ ml ](0.93GFR[ml / min/ m
2
] +15)
D[mg] = trgtAUC[mg - min/ ml] (GFR[ml / min] + (0.36 BW[kg]))
ADULTS
CHILDREN