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![Page 1: 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 Frank.](https://reader035.fdocument.pub/reader035/viewer/2022062516/56649dd95503460f94ace1d8/html5/thumbnails/1.jpg)
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
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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
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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
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0
5
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25
0 100 200 300 400 5000
5
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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
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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
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Effect =Effect =[Drug][Drug]
KKDD + [Drug] + [Drug]Maximal effectMaximal effect
[Drug][Drug]
KKDD + [Drug] + [Drug]
Dose-Effect RelationshipDose-Effect Relationship
Effect =Effect =Maximal effect • [Drug]Maximal effect • [Drug]
KKDD + [Drug] + [Drug]
Effect =Effect = Maximal effectMaximal effect if [Dose] >> Kif [Dose] >> KDD
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0
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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
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0
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1 10 100 10000
20
40
60
80
100
1 10 100 1000
Log Dose-Effect CurveLog Dose-Effect Curve
% of % of Maximal Maximal
EffectEffect
[Drug][Drug]
ECEC5050
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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
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0
20
40
60
80
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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
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Metformin Dose-ResponseMetformin Dose-Response
0
20
40
60
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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
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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
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Comparing Dose-Effect CurvesComparing Dose-Effect Curves
0
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1 10 100 10000
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40
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1 10 100 1000
% of % of Maximal Maximal
EffectEffect
[Drug][Drug]
Drug ADrug A
Drug CDrug C
Drug BDrug B
Effect =Effect =Maximal effect • [Drug]Maximal effect • [Drug]
KKDD + [Drug] + [Drug]
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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
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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
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Drug InteractionsDrug Interactions
0
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40
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80
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1 10 100 1000
% of % of Maximal Maximal
EffectEffect
[Drug][Drug]
AgonistAgonist
Agonist + competitive Agonist + competitive antagonistantagonist
Agonist + non-competitive Agonist + non-competitive antagonistantagonist
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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
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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
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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
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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
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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
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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
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0
20
40
60
80
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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
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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
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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
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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
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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
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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)
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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
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Concentration and Effect vs. TimeConcentration and Effect vs. Time
0
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0
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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
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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
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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)
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THE ENDTHE END
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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
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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
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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%
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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
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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
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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
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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
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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
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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
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Carboplatin Adaptive DosingCarboplatin Adaptive Dosing
ADULTSADULTS
CHILDRENCHILDREN