Download DOSE-EFFECT RELATIONSHIP

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
[%]
5
0
0
100
200
300
400
Erythropoietin Dose [units/kg]
Eschbach et al. NEJM 316:73-8, 1987
500
Drug-Receptor Interactions
Drug
Ligand-binding
domain
Drug-Receptor
Complex
k1
Effector domain
Receptor
k2
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
Maximal effect
100
80
% of
Maximal
Effect
60
40
20
0
0
200
EC50
400
[Drug]
600
800
Log Dose-Effect Curve
100
80
% of
Maximal
Effect
60
40
20
EC50
0
1
10
100
[Drug]
1000
Lidocaine Graded Dose-Effect
0
1
2
3
Analog
Pain Score 4
5
6
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
Theophylline [µM]
Rabe et al. Eur Respir J 8:637-42, 1995
1000
Metformin Dose-Response
3
2.5
80
2
60
1.5
40
1
20
0.5
0
0
500
1000
1500
2000
Dose [mg/d]
Garber et al. Am J Med 102:491-7, 1997
2500
Decrease in HbA1c from
Placebo [%]
Decrease in FPG from
Placebo [mg/dl]
100
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
Effect
Drug C
40
20
Effect =
Maximal effect • [Drug]
KD + [Drug]
0
1
10
100
[Drug]
1000
Thiopurine Cytotoxicity
100%
Thioguanine
S
80%
H 2N
Cytotoxic
Effect
N
N
Mercaptopurine
N
H
N
60%
S
N
N
N
40%
20%
0%
-9
10
10
-8
10
-7
10
Thiopurine [M]
Adamson et al. Leukemia Res 18:805-10, 1994
-6
10
-5
N
H
Thiopurine Metabolic Activation
MP
SH
N
N
6
N
N
N
TG
SH
N
6
H 2N
N
N
H
H
PRPP
PRPP
SH
SH
N
N
N
N
PO 4 CH 2
N
N
HO
N
N
PO 4 CH 2
O
HO
SH
N
N
H 2N
TIMP
HO
N
N
PO 4 CH 2
O
OH
SH
TXMP
HO
H 2N
N
N
(PO 4 )3 CH 2
O
OH
N
N
O
OH
TGMP
R
(d)TGTP
HO
Receptor-Mediated Effects
100
Agonist
80
60
%
Maximum 40
Effect
Partial agonist
20
Antagonist
0
1
10
100
[Drug]
1000
Drug Interactions
100
Agonist
Agonist + competitive
antagonist
80
% of 60
Maximal
Effect
40
Agonist + non-competitive
antagonist
20
0
1
10
100
[Drug]
1000
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
# of
Subjects
30
20
10
0
1
3
5
7
9
11
Threshold Dose
13
15
Cumulative Dose-Effect Curve
100
80
Cumulative %
of Subjects
60
40
20
0
1
3
5
7
9
Dose
11
13
15
Cumulative Dose-Effect Study
NO. OF
NO.
DOSE LEVEL
SUBJECTS
RESPONDING
% RESPONSE
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
0
1
3
5
7
8
9
10
0
10
30
50
70
80
90
100
Therapeutic and Toxic Effects
100
Therapeutic
80
%
Responding
Toxic
60
40
20
ED99
TD50
TD1
ED50
0
70 80 90100
200
Dose
300
Indices
Therapeutic Indices
Therapeutic Ratio =
Certain Safety Factor =
Standard Safety Margin =
TD50
ED50
TD1
ED99
= 2.5
= 1.3
TD1 - ED99
ED99
X 100 = 31%
Doxorubicin Cardiotoxicity
1.0
0.80
Probability
of CHF
0.60
0.40
0.20
0
0
200
400
600
800
Total Doxorubicin Dose [mg/m2]
von Hoff et al. Ann Intern Med 91:710-7, 1979
1000
Lidocaine Quantal Dose-Effect
100
ED90 = 490 mg
80
%
60
Achieving
Complete
Analgesia 40
ED50 = 400 mg
20
0
100
1000
Total Lidocaine Dose (mg)
Ferrante et al. Anesth Analg 82:91-7, 1996
Antihypertensive Dose-Effect
DOSE RANGE (MG)
DRUG
EARLY STUDIES
PRESENT DOSE
LOWEST EFFECTIVE
DOSE (MG)
Propranolol
Atenolol
Hydrochlorothiazide
Captropril
Methyldopa
160-5000
100-2000
50-400
75-1000
500-6000
160-320
50-100
25-50
50-150
500-3000
80
25
12.5
37.5
750
Johnston Pharmacol Ther 55:53-93, 1992
Antihypertensive Drugs
100
Desirable
Dose Range
Dose Range
most often used
80
% with
Maximal
Effect
60
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
Relative Dose Intensity
Hryniuk & Bush J Clin Oncol 2:1281, 1984
1
RDI
Relative Dose Intensity
DOSE
R.D.I.
REGIMEN DRUGS
RATE
DRUGS REGIMEN
mg/m2/wk
CAF-1
Cyclo
Adria
FU
350
15
250
1
1
1
1
CAF-2
Cyclo
Adria
FU
125
12.5
125
0.36
0.83
0.50
0.56
Doxorubicin Dose in Osteosarcoma
100
80
60
% with >90%
Necrosis
40
20
0
100
200
0
0
Smith et al. JNCI 83:1460, 1993
5
10
15
Dose Intensity (mg/m2/wk)
20
Relating Dose to Effect In Vivo
Dose
Effect site
Concentration
Effect
Pharmacokinetics
Pharmacodynamics
Age
Absorption
Distribution
Elimination
Drug interactions
Tissue/organ sensitivity
(receptor status)
Oral Mercaptopurine
5
AUC =
4
MP AUC
[µM•hr]
3
2
1
0
0
20
40
60
MP Dose (mg/m2)
Balis et al. Blood 92:3569-77, 1998
80
100
Dose • F
Clearance
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
k0
dCe k1e  C  Vc

 ke 0  Ce
dt
Ve
k1e
E max  CeH
E(t) 
H
EC50
 CeH
k10
ke0
Pharmacodynamic Models
 Fixed effect model
 Linear model
Effect = E0 + S•[Drug]
 Log-linear model
Effect = I + S•Log([Drug])
 Emax model
 Sigmoid Emax model
Effect =
Emax•[Drug]H
H
EC50
+ [Drug]H
Sigmoid Emax PD Model
Effect (%)
Effect (%)
H=5
100
100
H=2
H=1
80
80
H = 0.5
60
60
H = 0.1
40
40
20
20
EC50
0
EC50
0
0
20
40
60
80
100
1
[Drug]
10
100
Theophylline Pharmacodynamics
60
50
40
FEV1
30
(% normal)
20
Emax = 63%
10
EC50 = 10 mg/L
0
0
Mitenko & Ogilvie NEJM 289:600-3, 1973
5
10
15
20
25
Theophylline [mg/L]
30
Carboplatin PK/PD
% Decrease
Plt
Carboplatin
ClTB [ml/min]
140
100
120
90
100
80
80
60
70
40
60
20
0
50
40
45
50
55
60
65
70
Carboplatin AUC
[µg•hr/ml]
Van Echo et al. Semin Oncol 16:1-6, 1989
75
0
20
40
60
80
100 120 140
Creatinine Clearance
[ml/min]
Carboplatin Adaptive Dosing
ADULTS
prePlt  trgtPlt

D[mg / m 2 ]  0.091 CLCR[ml / min/ m 2 ]  
 100  priorRx 86

prePlt

D[mg]  trgtAUC[mg  min/ ml]  (GFR[ml / min]  25)
CHILDREN
D[mg / m 2 ]  trgtAUC[mg  min/ ml] (0.93  GFR[ml / min/ m 2 ] 15)
D[mg]  trgtAUC[mg  min/ ml]  (GFR[ml / min]  (0.36  BW[kg]))
Concentration and Effect vs. Time
Non-Steady State
10
100
Central
Compartment
8
80
Peripheral
Compartment
6
60
Conc./
Amount
Effect
4
2
40
Effect Compartment
20
0
0
0
5
10
15
Time
20
25
Effect
[% of EMAX]
Hysteresis and Proteresis Loops
Intensity of
Drug Effect
Intensity of
Drug Effect
Hysteresis Loop
(Counterclockwise)
4
4
• Equilibration delay in
plasma and effect site
conc.
3
• Tolerance
• Receptor tachyphylaxis
3
• Formation of active
metabolite
2
Proteresis Loop
(Clockwise)
2
• Receptor up-regulation
1
1
0
0
0
1
2
3
4
0
1
Plasma Drug Concentration
2
3
4
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