DOSE-EFFECT RELATIONSHIP

1
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
• Frank M. Balis, M.D.
• January 25, 2007

2
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

3
Dose-Effect Endpoints
Graded
Continuous scale (dose effect) Measured
in a single biologic unit Relates dose to
intensity of effect
Quantal
All-or-none pharmacologic effect Population
studies Relates dose to frequency of effect
4
Erythropoietin and Anemia
Peak Hematocrit Increment
Erythropoietin Dose units/kg
Eschbach et al. NEJM 31673-8, 1987
5
Drug-Receptor Interactions
Drug
Drug-Receptor Complex
Ligand-binding domain
k1
Effector domain
k2
Receptor
Effect
(KD k2/k1)
6
Dose-Effect Relationship
7
Graded Dose-Effect Curve
Maximal effect
of Maximal Effect
EC50
Drug
8
Log Dose-Effect Curve
of Maximal Effect
EC50
Drug
9
Lidocaine Graded Dose-Effect
Analog Pain Score
Lidocaine Blood Level µg/ml
Ferrante et al. Anesth Analg 8291-7, 1996
10
Theophylline Dose-Effect
Relaxation
Control
PDE Inhibition
Theophylline µM
Rabe et al. Eur Respir J 8637-42, 1995
11
Metformin Dose-Response
Decrease in FPG from Placebo mg/dl
Decrease in HbA1c from Placebo
Dose mg/d
Garber et al. Am J Med 102491-7, 1997
12
Dose-Effect Parameters
POTENCY
The sensitivity of an organ or tissue to the drug
EFFICACY
The maximum effect
13
Comparing Dose-Effect Curves
Drug A
Drug B
of Maximal Effect
Drug C
Drug
14
Thiopurine Cytotoxicity
Thioguanine
Mercaptopurine
Cytotoxic Effect
Thiopurine M
Adamson et al. Leukemia Res 18805-10, 1994
15
Receptor-Mediated Effects
Maximum Effect
Drug
16
Drug Interactions
Agonist
Agonist competitive antagonist
of Maximal Effect
Agonist non-competitive antagonist
Drug
17
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

18
Quantal Dose-Effect Distribution
ED50
of Subjects
Threshold Dose
19
Cumulative Dose-Effect Curve
Cumulative of Subjects
Dose
20
Cumulative Dose-Effect Study
Dose Level No. of Subjects No. 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
21
Therapeutic and Toxic Effects
Therapeutic
Toxic
Responding
ED99
TD50
TD1
ED50
Dose
Indices
22
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 91710-7, 1979
23
Lidocaine Quantal Dose-Effect
Achieving Complete Analgesia
Total Lidocaine Dose (mg)
Ferrante et al. Anesth Analg 8291-7, 1996
24
Antihypertensive Dose-Effect
Dose Range mg Dose Range mg Lowest Effective Dose mg
Drug Early Studies Present Dose Lowest Effective Dose mg
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
Johnston Pharmacol Ther 5553-93, 1992
25
Antihypertensive Drugs
Desirable Dose Range
Dose Range most often used
with Maximal Effect
Adverse Effects
Log Dose
26
Dose Intensity in Breast Cancer
Response Rate ()
Relative Dose Intensity
RDI
Hryniuk Bush J Clin Oncol 21281, 1984
27
Doxorubicin Dose in Osteosarcoma
100
80
60
with gt90 Necrosis
40
20
0
100
200
0
0
5
10
15
20
Dose Intensity (mg/m2/wk)
Smith et al. JNCI 831460, 1993
28
Relating Dose to Effect In Vivo
Dose
Effect
Age Absorption Distribution Elimination Drug
interactions
Tissue/organ sensitivity (receptor status)
29
Effect Compartment (PK/PD Model)
30
Concentration and Effect vs. Time
Non-Steady State
Central Compartment
Peripheral Compartment
Conc./ Amount
Effect of Emax
Effect
Effect Compartment
Time
31
Hysteresis and Proteresis Loops
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

Plasma Drug Concentration
32
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)

33
THE END
34
(No Transcript)
35
Endpoints to Monitor Drug Effect
Farnesyltransferase Inhibitors for Cancer
LEVEL ENDPOINT
Molecular Farnesyltransferase inhibition
Cellular Proliferation rate, apoptosis
Tumor Response (change in tumor size)
Organism Survival, quality of life
36
Thiopurine Metabolic Activation
37
Therapeutic Indices
Therapeutic Ratio
2.5
38
Relative Dose Intensity
Dose Rate mg/m2/wk R.D.I. R.D.I.
Regimen Drugs Dose Rate mg/m2/wk Drugs Regimen
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
39
Oral Mercaptopurine
MP AUC µMhr
MP Dose (mg/m2)
Balis et al. Blood 923569-77, 1998
40
Pharmacodynamic Models

• Fixed effect model
• Linear model
• Log-linear model
• Emax model
• Sigmoid Emax model

Effect E0 SDrug
Effect I SLog(Drug)
41
Sigmoid Emax PD Model
Effect ()
Effect ()
H 5
H 2
H 1
H 0.5
H 0.1
EC50
EC50
Drug
42
Theophylline Pharmacodynamics
FEV1 ( normal)
Emax 63 EC50 10 mg/L
Theophylline mg/L
Mitenko Ogilvie NEJM 289600-3, 1973
43
Carboplatin PK/PD
Decrease Platelet
Carboplatin ClTB ml/min
Creatinine Clearance ml/min
Carboplatin AUC µghr/ml
Van Echo et al. Semin Oncol 161-6, 1989
44
Carboplatin Adaptive Dosing
ADULTS
CHILDREN