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
 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
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
 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
 Erythropoietin and Anemia

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

Maximal effect • [Drug]

Effect =
KD + [Drug]
(KD = k2/k1)
 Dose-Effect Relationship

Maximal effect • [Drug]

Effect =
KD + [Drug]

[Drug]
Effect = Maximal effect
KD + [Drug]

Effect = Maximal effect if [Dose] >> KD

 Graded Dose-Effect Curve
100 Maximal effect

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

Decrease in HbA1c from

Decrease in FPG from

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

POTENCY: The sensitivity of an organ or

tissue to the drug

EFFICACY: The maximum effect

 Comparing Dose-Effect Curves
100
Drug A
Drug B
80

% of 60
Maximal Drug C
Effect
40

20 Maximal effect • [Drug]

Effect =
KD + [Drug]
0
1 10 100 1000
[Drug]
 Thiopurine Cytotoxicity

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

 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
50
ED50

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

DOSE RANGE (MG)

LOWEST EFFECTIVE
DRUG EARLY STUDIES PRESENT DOSE DOSE (MG)
Propranolol 160-5000 160-320 80
Atenolol 100-2000 50-100 25
Hydrochlorothiazide 50-400 25-50 12.5
Captropril 75-1000 50-150 37.5
Methyldopa 500-6000 500-3000 750

Johnston Pharmacol Ther 55:53-93, 1992

 Antihypertensive Drugs
Desirable
100 Dose Range
Dose Range
most often used

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

 Fixed effect model

 Linear model Effect = E0 + S•[Drug]

 Log-linear model Effect = I + S•Log([Drug])

 Emax model Emax•[Drug]H

Effect =
 Sigmoid Emax model EC50
H + [Drug]H
 Sigmoid Emax PD Model

Effect (%) Effect (%)

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

Carboplatin AUC Creatinine Clearance

[µg•hr/ml] [ml/min]
Van Echo et al. Semin Oncol 16:1-6, 1989
Carboplatin Adaptive Dosing

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