dose-effect relationship the intensity and duration of a drug’s effects are a function of the drug...

DOSE-EFFECT RELATIONSHIPDOSE-EFFECT RELATIONSHIP

The intensity and duration of a drug’s The intensity and duration of a drug’s effects are a function of the drug dose effects are a function of the drug dose

and drug concentration at the effect siteand drug concentration at the effect site

Frank M. Balis, M.D.Frank M. Balis, M.D.

January 25, 2007January 25, 2007

Monitoring Dose-EffectMonitoring Dose-Effect

• LevelLevel– Molecular (e.g, enzyme inhibition)Molecular (e.g, enzyme inhibition)

– Cellular (Cellular (in vitroin vitro tissue culture, blood cells) tissue culture, blood cells)

– Tissue or organ (Tissue or organ (in vitroin vitro or or in vivoin vivo))

– OrganismOrganism

• Endpoint used to measure effect may be Endpoint used to measure effect may be different at each leveldifferent at each level

• Overall effect = sum of multiple drug effects Overall effect = sum of multiple drug effects and physiological response to drug effectsand physiological response to drug effects

Dose-Effect EndpointsDose-Effect Endpoints

GradedGraded

QuantalQuantal

•• Continuous scaleContinuous scale ( (dosedose effect)effect)

•• Measured in a single biologic unitMeasured in a single biologic unit

•• Relates dose to intensity of effectRelates dose to intensity of effect

•• All-or-none pharmacologic effectAll-or-none pharmacologic effect

•• Population studiesPopulation studies

•• Relates dose to frequency of effectRelates dose to frequency of effect

0

5

10

15

20

25

0 100 200 300 400 5000

5

10

15

20

25

0 100 200 300 400 500

Erythropoietin and AnemiaErythropoietin and Anemia

Erythropoietin Dose [units/kg]Erythropoietin Dose [units/kg]

Peak Peak Hematocrit Hematocrit Increment Increment

[%][%]

Eschbach et al. NEJM 316:73-8, 1987Eschbach et al. NEJM 316:73-8, 1987

Drug-Receptor InteractionsDrug-Receptor Interactions

kk11

kk22

DrugDrug

ReceptorReceptor

EffectEffect

Drug-Drug-Receptor Receptor ComplexComplex

Effect =Effect =Maximal effect • [Drug]Maximal effect • [Drug]

KKDD + [Drug] + [Drug]

(K(KDD = k = k22/k/k11))

Ligand-binding Ligand-binding domain domain

Effector domain Effector domain

Effect =Effect =[Drug][Drug]

KKDD + [Drug] + [Drug]Maximal effectMaximal effect

[Drug][Drug]


Dose-Effect RelationshipDose-Effect Relationship



Effect =Effect = Maximal effectMaximal effect if [Dose] >> Kif [Dose] >> KDD

0

20

40

60

80

100

0 200 400 600 8000

20

40

60

80

100

0 200 400 600 800

Graded Dose-Effect CurveGraded Dose-Effect Curve

% of % of Maximal Maximal

EffectEffect

[Drug][Drug]ECEC5050

Maximal effectMaximal effect

0

20

40

60

80

100

1 10 100 10000

20

40

60

80

100

1 10 100 1000

Log Dose-Effect CurveLog Dose-Effect Curve


EffectEffect

[Drug][Drug]

ECEC5050

0

1

2

3

4

5

6

7

0 1 2 3

0

1

2

3

4

5

6

7

0 1 2 3

Lidocaine Graded Dose-EffectLidocaine Graded Dose-Effect

Lidocaine Blood Level [µg/ml]Lidocaine Blood Level [µg/ml]

AnalogAnalogPain ScorePain Score

Ferrante et al. Anesth Analg 82:91-7, 1996Ferrante et al. Anesth Analg 82:91-7, 1996

0

20

40

60

80

100

1 10 100 10000

20

40

60

80

100

1 10 100 1000

Theophylline Dose-EffectTheophylline Dose-Effect

PDE InhibitionPDE Inhibition

RelaxationRelaxation

% ControlControl

Theophylline [µM]Theophylline [µM]Rabe et al. Eur Respir J 8:637-42, 1995Rabe et al. Eur Respir J 8:637-42, 1995

Metformin Dose-ResponseMetformin Dose-Response

0

20

40

60

80

100

0

0.5

1

1.5

2

2.5

3

500 1000 1500 2000 25000

20

40

60

80

100

0

0.5

1

1.5

2

2.5

3

500 1000 1500 2000 2500

Dec

reas

e in

FP

G f

rom

Pla

ceb

o D

ecre

ase

in F

PG

fro

m P

lace

bo

[mg/

dl]

[mg/

dl]

Decrease in

Hb

AD

ecrease in H

bA

1c1c from

from

Placeb

o [%]

Placeb

o [%]

Dose [mg/d]Dose [mg/d]Garber et al. Am J Med 102:491-7, 1997Garber et al. Am J Med 102:491-7, 1997

Dose-Effect ParametersDose-Effect Parameters

PPOTENCYOTENCY::

EEFFICACYFFICACY::

The sensitivity of an organ or The sensitivity of an organ or tissue to the drugtissue to the drug

The maximum effectThe maximum effect

Comparing Dose-Effect CurvesComparing Dose-Effect Curves

0

20

40

60

80

100

1 10 100 10000

20

40

60

80

100

1 10 100 1000


EffectEffect

[Drug][Drug]

Drug ADrug A

Drug CDrug C

Drug BDrug B



Thiopurine CytotoxicityThiopurine Cytotoxicity

0%

20%

40%

60%

80%

100%

10-9 10-8 10-7 10-6 10-50%

20%

40%

60%

80%

100%

10-9 10-8 10-7 10-6 10-5

Cytotoxic Cytotoxic EffectEffect

Thiopurine [M]Thiopurine [M]

ThioguanineThioguanine

MercaptopurineMercaptopurineN

N N

N

HH2N

S

N

N N

N

HH2N

S

N

N N

N

H

S

N

N N

N

H

S

Adamson et al. Leukemia Res 18:805-10, 1994Adamson et al. Leukemia Res 18:805-10, 1994

Receptor-Mediated EffectsReceptor-Mediated Effects

% % Maximum Maximum

EffectEffect

[Drug][Drug]

Agonist

Antagonist

Partial agonist

100

80

60

40

20

0

1 10010 1000

Agonist

Antagonist

Partial agonist

100

80

60

40

20

0

1 10010 1000

Drug InteractionsDrug Interactions

0

20

40

60

80

100

1 10 100 10000

20

40

60

80

100

1 10 100 1000


EffectEffect

[Drug][Drug]

AgonistAgonist

Agonist + competitive Agonist + competitive antagonistantagonist

Agonist + non-competitive Agonist + non-competitive antagonistantagonist

Graded Dose-Effect AnalysisGraded Dose-Effect Analysis

• Identify the therapeutic dose/concentrationIdentify the therapeutic dose/concentration

• Define site of drug action (receptor)Define site of drug action (receptor)

• Classify effect produced by drug-receptor Classify effect produced by drug-receptor interaction (agonist, antagonist)interaction (agonist, antagonist)

• Compare the relative potency and efficacy of Compare the relative potency and efficacy of drugs that produce the same effectdrugs that produce the same effect

• Assess mechanism of drug interactionsAssess mechanism of drug interactions

Quantal Dose-Effect DistributionQuantal Dose-Effect Distribution

Threshold DoseThreshold Dose

# of# ofSubjectsSubjects

0

10

20

30

40

50

1 3 5 7 9 11 13 150

10

20

30

40

50

1 3 5 7 9 11 13 15

EDED5050

Cumulative Dose-Effect CurveCumulative Dose-Effect Curve

DoseDose

Cumulative Cumulative % of % of

SubjectsSubjects

0

20

40

60

80

100

1 3 5 7 9 11 13 150

20

40

60

80

100

1 3 5 7 9 11 13 15

Cumulative Dose-Effect StudyCumulative Dose-Effect Study

Dose LevelDose LevelNo. of No. of

SubjectsSubjectsNo. No.

RespondingResponding% %

ResponseResponse11 1010 00 00

22 1010 11 1010

33 1010 33 3030

44 1010 55 5050

55 1010 77 7070

66 1010 88 8080

77 1010 99 9090

88 1010 1010 100100

0

20

40

60

80

100

70 80 90100 200 3000

20

40

60

80

100

70 80 90100 200 300

Therapeutic and Toxic EffectsTherapeutic and Toxic Effects

DoseDose

% % RespondingResponding

TherapeuticTherapeutic

ToxicToxic

EDED9999

TDTD11EDED5050

TDTD5050

IndicesIndices

Doxorubicin CardiotoxicityDoxorubicin Cardiotoxicity

Total Doxorubicin Dose [mg/mTotal Doxorubicin Dose [mg/m22]]

Probability Probability of CHFof CHF

00

0.200.20

0.400.40

0.600.60

0.800.80

1.01.0

00 200200 400400 600600 800800 10001000

von Hoff et al. Ann Intern Med 91:710-7, 1979von Hoff et al. Ann Intern Med 91:710-7, 1979

0

20

40

60

80

100

100 10000

20

40

60

80

100

100 1000

Lidocaine Quantal Dose-EffectLidocaine Quantal Dose-Effect

% % Achieving Achieving Complete Complete AnalgesiaAnalgesia

Total Lidocaine Dose (mg)Total Lidocaine Dose (mg)Ferrante et al. Anesth Analg 82:91-7, 1996Ferrante et al. Anesth Analg 82:91-7, 1996

EDED5050 = 400 mg = 400 mg

EDED9090 = 490 mg = 490 mg

Antihypertensive Dose-EffectAntihypertensive Dose-Effect

Johnston Pharmacol Ther 55:53-93, 1992Johnston Pharmacol Ther 55:53-93, 1992

Dose Range [mg]Dose Range [mg]

Lowest Effective Lowest Effective Dose [mg]Dose [mg]DrugDrug Early StudiesEarly Studies Present DosePresent Dose

PropranololPropranolol 160-5000160-5000 160-320160-320 8080

AtenololAtenolol 100-2000100-2000 50-10050-100 2525

HydrochlorthiazideHydrochlorthiazide 50-40050-400 25-5025-50 12.512.5

CaptoprilCaptopril 75-100075-1000 50-15050-150 37.537.5

MethyldopaMethyldopa 500-6000500-6000 500-3000500-3000 750750

Antihypertensive DrugsAntihypertensive Drugs

0

20

40

60

80

100

0

20

40

60

80

100

Log DoseLog Dose

% with % with Maximal Maximal

EffectEffect Adverse Adverse EffectsEffects

Desirable Desirable Dose RangeDose Range

Dose Range Dose Range most often usedmost often used

Dose Intensity in Breast CancerDose Intensity in Breast Cancer

0

20

40

60

80

100

0 0.2 0.4 0.6 0.8 10

20

40

60

80

100

0 0.2 0.4 0.6 0.8 1

Response Response Rate (%)Rate (%)

Relative Dose IntensityRelative Dose Intensity RDIRDIHryniuk & Bush J Clin Oncol 2:1281, 1984Hryniuk & Bush J Clin Oncol 2:1281, 1984

Doxorubicin Dose in OsteosarcomaDoxorubicin Dose in Osteosarcoma

Dose Intensity (mg/mDose Intensity (mg/m22/wk)/wk)

% with % with >90% >90%

NecrosisNecrosis

Smith et al. JNCI 83:1460, 1993Smith et al. JNCI 83:1460, 1993

00 100100 200200

00 55 1010 1515 202000

2020

4040

6060

8080

100100

Relating Dose to Effect Relating Dose to Effect In VivoIn Vivo

DoseDose EffectEffectEffect site Effect site ConcentrationConcentration

Pharmacokinetics Pharmacodynamics

AgeAge

AbsorptionAbsorption

DistributionDistribution

Elimination Elimination

Drug interactionsDrug interactions

Tissue/organ sensitivity Tissue/organ sensitivity (receptor status)(receptor status)

Effect Compartment (PK/PD Model)Effect Compartment (PK/PD Model)

k0 k1e

k10 ke0

Central Effect

Peripheral

k12k21

k0 k1e

k10 ke0

Central Effect

Peripheral

k12k21

dCdt

k0

Vc (k10 k12) C

k21 XpVc

dX pdt

k12 C Vc k21 X p

dCedt

k1e C VcVe

ke0 Ce

E( t) Emax Ce

H

EC50H Ce

H

Concentration and Effect vs. TimeConcentration and Effect vs. Time

0

2

4

6

8

10

0

20

40

60

80

100

0 5 10 15 20 25

0

2

4

6

8

10

0

20

40

60

80

100

0 5 10 15 20 25

Conc./ Conc./ AmountAmount

EffectEffect[% of E[% of Emaxmax]]

TimeTime

Central Central CompartmentCompartment

Peripheral Peripheral CompartmentCompartment

Effect CompartmentEffect Compartment

EffectEffect

Non-Steady StateNon-Steady State

Hysteresis and Proteresis LoopsHysteresis and Proteresis Loops

0

1

2

3

4

0 1 2 3 40

1

2

3

4

0 1 2 3 40

1

2

3

4

0 1 2 3 40

1

2

3

4

0 1 2 3 4

Plasma Drug ConcentrationPlasma Drug Concentration

Intensity of Intensity of Drug EffectDrug Effect

Intensity of Intensity of Drug EffectDrug EffectHysteresis Loop Hysteresis Loop

(Counterclockwise)(Counterclockwise)Proteresis Loop Proteresis Loop

(Clockwise)(Clockwise)

• Equilibration delay in Equilibration delay in plasma and effect site conc.plasma and effect site conc.

• Formation of active Formation of active metabolitemetabolite

• Receptor up-regulationReceptor up-regulation

• ToleranceTolerance

• Receptor tachyphylaxisReceptor tachyphylaxis

Role of Dose-Effect StudiesRole of Dose-Effect Studies

• Drug developmentDrug development– Site of actionSite of action

– Selection of dose and scheduleSelection of dose and schedule

– Potency, efficacy and safetyPotency, efficacy and safety

– Drug interactionsDrug interactions

• Patient managementPatient management– Therapeutic drug monitoringTherapeutic drug monitoring

– Risk-benefit (therapeutic indices)Risk-benefit (therapeutic indices)

THE ENDTHE END

Endpoints to Monitor Drug EffectEndpoints to Monitor Drug Effect

LLEVELEVEL EENDPOINTNDPOINT

MolecularMolecular Farnesyltransferase inhibitionFarnesyltransferase inhibition

CellularCellular Proliferation rate, apoptosisProliferation rate, apoptosis

TumorTumor Response (change in tumor size)Response (change in tumor size)

OrganismOrganism Survival, quality of lifeSurvival, quality of life

Farnesyltransferase Inhibitors for CancerFarnesyltransferase Inhibitors for Cancer

Thiopurine Metabolic ActivationThiopurine Metabolic Activation

6

OPO4CH2

SH

N

NN

N

OHHO

O(PO4)3CH2

SH

N

NN

N

H2N

HO R

OPO4CH2

SH

N

NN

N

OHHO

H2N

OPO4CH2

SH

N

NN

N

OHHO

HO

MP TG

TIMP TGMPTXMP (d)TGTP

6

PRPPPRPP

N

N N

N

SH

H2N

H

N

N N

N

SH

H

6

OPO4CH2

SH

N

NN

N

OHHO

O(PO4)3CH2

SH

N

NN

N

H2N

HO R

OPO4CH2

SH

N

NN

N

OHHO

H2N

OPO4CH2

SH

N

NN

N

OHHO

HO

MP TG

TIMP TGMPTXMP (d)TGTP

6

PRPPPRPP

N

N N

N

SH

H2N

H

N

N N

N

SH

H

Therapeutic IndicesTherapeutic Indices

Therapeutic Ratio =Therapeutic Ratio =TDTD5050

EDED5050

= 2.5= 2.5

Certain Safety Factor =Certain Safety Factor =TDTD11

EDED9999

= 1.3= 1.3

Standard Safety Margin =Standard Safety Margin =TDTD11 - ED - ED9999

EDED9999

XX 100 = 31% 100 = 31%

Relative Dose IntensityRelative Dose Intensity

Dose Rate Dose Rate mg/mmg/m22/wk/wk

R.D.I.R.D.I.

RegimenRegimen DrugsDrugs DrugsDrugs RegimenRegimen

CycloCyclo 350350 11

CAF-1CAF-1 DoxoDoxo 1515 11 11

FUFU 250250 11

CycloCyclo 125125 0.360.36

CAF-2CAF-2 DoxoDoxo 12.512.5 0.830.83 0.560.56

FUFU 125125 0.500.50

Oral MercaptopurineOral Mercaptopurine

0

1

2

3

4

5

0 20 40 60 80 1000

1

2

3

4

5

0 20 40 60 80 100

MP Dose (mg/mMP Dose (mg/m22))

MP AUC MP AUC [µM•hr][µM•hr]

AUC =AUC =ClearanceClearanceDose • FDose • F

Balis et al. Blood 92:3569-77, 1998Balis et al. Blood 92:3569-77, 1998

Pharmacodynamic ModelsPharmacodynamic Models

• Fixed effect modelFixed effect model

• Linear modelLinear model

• Log-linear modelLog-linear model

• EEmaxmax model model

• Sigmoid ESigmoid Emaxmax model model

Effect = EEffect = E00 + S•[Drug] + S•[Drug]

Effect = I + S•Log([Drug])Effect = I + S•Log([Drug])

Effect = Effect = ECEC5050 + [Drug] + [Drug]HH

EEmaxmax•[Drug]•[Drug]HH

HH

Sigmoid ESigmoid Emaxmax PD Model PD Model

0

20

40

60

80

100

0 20 40 60 80 1000

20

40

60

80

100

0 20 40 60 80 1000

20

40

60

80

100

1 10 1000

20

40

60

80

100

1 10 100

[Drug][Drug]

Effect (%)Effect (%) Effect (%)Effect (%)

ECEC5050ECEC5050

H = 0.1H = 0.1

H = 5H = 5

H = 2H = 2H = 1H = 1

H = 0.5H = 0.5

Theophylline PharmacodynamicsTheophylline Pharmacodynamics

0

10

20

30

40

50

60

0 5 10 15 20 25 300

10

20

30

40

50

60

0 5 10 15 20 25 30

Theophylline [mg/L]Theophylline [mg/L]

FEVFEV11

(% normal)(% normal)

EEmaxmax = 63% = 63%

ECEC5050 = 10 mg/L = 10 mg/L

Mitenko & Ogilvie NEJM 289:600-3, 1973Mitenko & Ogilvie NEJM 289:600-3, 1973

Carboplatin PK/PDCarboplatin PK/PD

50

60

70

80

90

100

40 45 50 55 60 65 70 7550

60

70

80

90

100

40 45 50 55 60 65 70 750

20

40

60

80

100

120

140

0 20 40 60 80 100 120 1400

20

40

60

80

100

120

140

0 20 40 60 80 100 120 140

Carboplatin AUC Carboplatin AUC [µg•hr/ml][µg•hr/ml]

Creatinine Clearance Creatinine Clearance [ml/min][ml/min]

% Decrease % Decrease PlateletPlatelet

Carboplatin Carboplatin ClClTBTB [ml/min] [ml/min]

Van Echo et al. Semin Oncol 16:1-6, 1989Van Echo et al. Semin Oncol 16:1-6, 1989

Carboplatin Adaptive DosingCarboplatin Adaptive Dosing

ADULTSADULTS

CHILDRENCHILDREN

dose-effect relationship the intensity and duration of a drug’s effects are a function of the drug...

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