Académique Documents
Professionnel Documents
Culture Documents
Level
• Molecular (e.g, enzyme inhibition)
• Cellular (in vitro tissue culture, blood cells)
• Tissue or organ (in vitro or in vivo)
• Organism
LEVEL ENDPOINT
Molecular Farnesyltransferase inhibition
Cellular Proliferation rate, apoptosis
25
20
Peak 15
Hematocrit
Increment
[%] 10
0
0 100 200 300 400 500
Erythropoietin Dose [units/kg]
Eschbach et al. NEJM 316:73-8, 1987
Drug-Receptor Interactions
Drug Drug-Receptor
Complex
Ligand-binding
domain
k1
Effector k2
domain Receptor
Effect
[Drug]
Effect = Maximal effect
KD + [Drug]
80
% of 60
Maximal
Effect 40
20
0
0 200 400 600 800
EC50
[Drug]
Log Dose-Effect Curve
100
80
% of 60
Maximal
Effect 40
20
EC50
0
1 10 100 1000
[Drug]
Lidocaine Graded Dose-Effect
3
Analog
Pain Score 4
7
0 1 2 3
Lidocaine Blood Level [µg/ml]
Ferrante et al. Anesth Analg 82:91-7, 1996
Theophylline Dose-Effect
100
Relaxation
80
60
% Control PDE Inhibition
40
20
0
1 10 100 1000
Theophylline [µM]
Rabe et al. Eur Respir J 8:637-42, 1995
Metformin Dose-Response
100 3
2.5
80
Placebo [mg/dl]
Placebo [%]
60
1.5
40
1
20
0.5
0 0
500 1000 1500 2000 2500
Dose [mg/d]
Garber et al. Am J Med 102:491-7, 1997
Dose-Effect Parameters
% of 60
Maximal Drug C
Effect
40
100%
Thioguanine
S
80% N N
Mercaptopurine
H22N
N N
N N
S
H
60% N
N
Cytotoxic
N
Effect N
H
40%
20%
0%
-9 -8 -7 -6 -5
10 10 10 10 10
Thiopurine [M]
Adamson et al. Leukemia Res 18:805-10, 1994
Thiopurine Metabolic Activation
SH MP SH TG
N N
N 6 N 6
N N H 22N N N
H H
PRPP PRPP
SH SH SH SH
N N N N
N N N N
N N N N
N HO N H2 N N H 22N N
PO44CH 22 PO44CH 22 PO44CH 22 (PO44)3 CH 22
O O O O
HO OH HO OH HO OH HO R
TIMP TXMP TGMP
(d)TGTP
Receptor-Mediated Effects
100
Agonist
80
60
%
Maximum 40 Partial agonist
Effect
20
Antagonist
0
1 10 100 1000
[Drug]
Drug Interactions
100
Agonist
Agonist + competitive
80 antagonist
% of 60
Maximal
Effect
40 Agonist + non-competitive
antagonist
20
0
1 10 100 1000
[Drug]
Graded Dose-Effect Analysis
40
30
# of
Subjects
20
10
0
1 3 5 7 9 11 13 15
Threshold Dose
Cumulative Dose-Effect Curve
100
80
60
Cumulative %
of Subjects
40
20
0
1 3 5 7 9 11 13 15
Dose
Cumulative Dose-Effect Study
NO. OF NO.
DOSE LEVEL SUBJECTS RESPONDING % 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
Therapeutic and Toxic Effects
100
Therapeutic
80 Toxic
60
%
Responding
40
20 ED99
TD1 TD50
ED50
0
70 80 90100 200 300
Dose Indices
Therapeutic Indices
TD50
Therapeutic Ratio = = 2.5
ED50
TD1
Certain Safety Factor = = 1.3
ED99
TD1 - ED99
Standard Safety Margin = X 100 = 31%
ED99
Doxorubicin Cardiotoxicity
1.0
0.80
0.60
Probability
of CHF
0.40
0.20
0
0 200 400 600 800 1000
Total Doxorubicin Dose [mg/m2]
von Hoff et al. Ann Intern Med 91:710-7, 1979
Lidocaine Quantal Dose-Effect
100
ED90 = 490 mg
80
% 60
Achieving
ED50 = 400 mg
Complete
Analgesia 40
20
0
100 1000
Total Lidocaine Dose (mg)
Ferrante et al. Anesth Analg 82:91-7, 1996
Antihypertensive Dose-Effect
80
% with 60
Maximal
Effect 40
Adverse
Effects
20
0
Log Dose
Dose Intensity in Breast Cancer
100
80
60
Response
Rate (%)
40
20
0
0 0.2 0.4 0.6 0.8 1
Relative Dose Intensity
RDI
Hryniuk & Bush J Clin Oncol 2:1281, 1984
Relative Dose Intensity
Doxorubicin Dose in Osteosarcoma
100
80
60
% with >90%
Necrosis
40
20 0 100 200
0
0 5 10 15 20
Dose Intensity (mg/m2/wk)
Smith et al. JNCI 83:1460, 1993
Relating Dose to Effect In Vivo
Effect site
Dose Concentration
Effect
Pharmacokinetics Pharmacodynamics
Age Tissue/organ sensitivity
Absorption (receptor status)
Distribution
Elimination
Drug interactions
Oral Mercaptopurine
5 Dose • F
AUC =
Clearance
3
MP AUC
[µM•hr]
2
0
0 20 40 60 80 100
MP Dose (mg/m2)
Balis et al. Blood 92:3569-77, 1998
Effect Compartment (PK/PD Model)
Peripheral
dX p
k12 C Vc k21 X p
dt
k21 k12
dC k0 k Xp
(k10 k12 ) C 21
dt Vc Vc
Central Effect
dCe k1e C Vc
k0 k1e ke 0 Ce
dt Ve
E max CeH
E(t) H
EC 50 CeH
k10 ke0
Pharmacodynamic Models
100
H=5 100
H=2
80 H=1 80
H = 0.5
60 60
H = 0.1
40 40
20 20
EC50 EC50
0 0
0 20 40 60 80 100 1 10 100
[Drug]
Theophylline Pharmacodynamics
60
50
40
FEV1
30
(% normal)
20 Emax = 63%
10 EC50 = 10 mg/L
0
0 5 10 15 20 25 30
Theophylline [mg/L]
Mitenko & Ogilvie NEJM 289:600-3, 1973
Carboplatin PK/PD
% Decrease Carboplatin
Plt ClTB [ml/min]
100 140
120
90
100
80 80
60
70
40
60
20
50 0
40 45 50 55 60 65 70 75 0 20 40 60 80 100 120 140
ADULTS
CHILDREN
Concentration and Effect vs. Time
Non-Steady State
10 100
Central
8 Compartment 80
Peripheral
6 Compartment
60
Conc./ Effect
Amount [% of EMAX]
4 Effect
40
2
Effect Compartment 20
0
0
0 5 10 15 20 25
Time
Hysteresis and Proteresis Loops
Intensity of Intensity of
Drug Effect Hysteresis Loop Drug Effect Proteresis Loop
4 (Counterclockwise) 4 (Clockwise)
• Equilibration delay in • Tolerance
plasma and effect site
3 3 • Receptor tachyphylaxis
conc.
• Formation of active
2 metabolite 2
• Receptor up-regulation
1 1
0 0
0 1 2 3 4 0 1 2 3 4
Plasma Drug Concentration
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