Professional Documents
Culture Documents
1. General Principles
2. Peripheral Nervous Pharmacology
3. Central Nervous Pharmacology
4. Cardiovascular Pharmacology
5. Splanchnic Pharmacology
6. Endocrine Pharmacology
7. Chemotherapeutic Pharmacology
DOSE-EFFECT RELATIONSHIP
The intensity and duration of a drug’s
effects are a function of the drug dose and
drug concentration at the effect site
Endpoints to Monitor Drug Effect
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 domain
k2
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