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 M. Balis, M.D. January 25, 2007

Monitoring Dose-Effect LevelLevel –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 levelEndpoint used to measure effect may be different at each level Overall effect = sum of multiple drug effects and physiological response to drug effectsOverall effect = sum of multiple drug effects and physiological response to drug effects

Dose-Effect Endpoints Graded Quantal Continuous scale (  dose   effect)Continuous scale (  dose   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

Erythropoietin and Anemia Erythropoietin Dose [units/kg] Peak Hematocrit Increment [%] Eschbach et al. NEJM 316:73-8, 1987

Drug-Receptor Interactions k1k1k1k1 k2k2k2k2 Drug Receptor Effect Drug-Receptor Complex Effect = Maximal effect [Drug] K D + [Drug] (K D = k 2 /k 1 ) Ligand-binding domain Effector domain

Effect = [Drug] K D + [Drug] Maximal effect [Drug] K D + [Drug] Dose-Effect Relationship Effect = Maximal effect [Drug] K D + [Drug] Effect = Maximal effect if [Dose] >> K D if [Dose] >> K D

Graded Dose-Effect Curve % of Maximal Effect [Drug] EC 50 Maximal effect

Log Dose-Effect Curve % of Maximal Effect [Drug] EC 50

Lidocaine Graded Dose-Effect Lidocaine Blood Level [µg/ml] Analog Pain Score Ferrante et al. Anesth Analg 82:91-7, 1996

Theophylline Dose-Effect PDE Inhibition Relaxation Control % Control Theophylline [µM] Rabe et al. Eur Respir J 8:637-42, 1995

Metformin Dose-Response Decrease in FPG from Placebo [mg/dl] Decrease in HbA 1c from Placebo [%] Dose [mg/d] Garber et al. Am J Med 102:491-7, 1997

Dose-Effect Parameters P OTENCY : E FFICACY : The sensitivity of an organ or tissue to the drug The maximum effect

Comparing Dose-Effect Curves % of Maximal Effect [Drug] Drug A Drug C Drug B Effect = Maximal effect [Drug] K D + [Drug]

Thiopurine Cytotoxicity Cytotoxic Effect Thiopurine [M] Thioguanine Mercaptopurine Adamson et al. Leukemia Res 18:805-10, 1994

Receptor-Mediated Effects % Maximum Effect [Drug]

Drug Interactions % of Maximal Effect [Drug] Agonist Agonist + competitive antagonist Agonist + non-competitive antagonist

Graded 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 interaction (agonist, antagonist)Classify effect produced by drug-receptor interaction (agonist, antagonist) Compare the relative potency and efficacy of drugs that produce the same effectCompare the relative potency and efficacy of drugs that produce the same effect Assess mechanism of drug interactionsAssess mechanism of drug interactions

Quantal Dose-Effect Distribution Threshold Dose # of Subjects ED 50

Cumulative Dose-Effect Curve Dose Cumulative % of Subjects

Cumulative Dose-Effect Study Dose Level No. of Subjects No. Responding % Response

Therapeutic and Toxic Effects Dose % Responding Therapeutic Toxic ED 99 TD 1 ED 50 TD 50

Doxorubicin Cardiotoxicity Total Doxorubicin Dose [mg/m 2 ] Probability of CHF von Hoff et al. Ann Intern Med 91:710-7, 1979

Lidocaine Quantal Dose-Effect % Achieving Complete Analgesia Total Lidocaine Dose (mg) Ferrante et al. Anesth Analg 82:91-7, 1996 ED 50 = 400 mg ED 90 = 490 mg

Antihypertensive Dose-Effect Johnston Pharmacol Ther 55:53-93, 1992 Dose Range [mg] Lowest Effective Dose [mg] Drug Early Studies Present Dose Propranolol Atenolol Hydrochlorthiazide Captopril Methyldopa

Antihypertensive Drugs Log Dose % with Maximal Effect Adverse Effects Desirable Dose Range Dose Range most often used

Dose Intensity in Breast Cancer Response Rate (%) Relative Dose Intensity Hryniuk & Bush J Clin Oncol 2:1281, 1984

Doxorubicin Dose in Osteosarcoma Dose Intensity (mg/m 2 /wk) % with >90% Necrosis Smith et al. JNCI 83:1460,

Relating Dose to Effect In Vivo DoseEffect Effect site Concentration PharmacokineticsPharmacodynamics AgeAbsorptionDistributionElimination Drug interactions Tissue/organ sensitivity (receptor status)

Effect Compartment (PK/PD Model)

Concentration and Effect vs. Time Conc./ Amount Effect [% of E max ] Time Central Compartment Peripheral Compartment Effect Compartment Effect Non-Steady State

Hysteresis and Proteresis Loops Plasma Drug Concentration Intensity of Drug Effect Hysteresis Loop (Counterclockwise) Proteresis Loop (Clockwise) Equilibration delay in plasma and effect site conc.Equilibration delay in plasma and effect site conc. Formation of active metaboliteFormation of active metabolite Receptor up-regulationReceptor up-regulation ToleranceTolerance Receptor tachyphylaxisReceptor tachyphylaxis

Role of Dose-Effect Studies Drug developmentDrug development –Site of action –Selection of dose and schedule –Potency, efficacy and safety –Drug interactions Patient managementPatient management –Therapeutic drug monitoring –Risk-benefit (therapeutic indices)

THE END

Endpoints to Monitor Drug Effect L EVEL E NDPOINT Molecular Farnesyltransferase inhibition Cellular Proliferation rate, apoptosis Tumor Response (change in tumor size) Organism Survival, quality of life Farnesyltransferase Inhibitors for Cancer

Thiopurine Metabolic Activation

Therapeutic Indices Therapeutic Ratio = TD 50 ED 50 = 2.5 Certain Safety Factor = TD 1 ED 99 = 1.3 Standard Safety Margin = TD 1 - ED 99 ED 99 X 100 = 31%

Relative Dose Intensity Dose Rate mg/m 2 /wk R.D.I. RegimenDrugsDrugsRegimen Cyclo3501 CAF-1Doxo1511 FU2501 Cyclo CAF-2Doxo FU

Oral Mercaptopurine MP Dose (mg/m 2 ) MP AUC [µMhr] AUC = Clearance Dose F Balis et al. Blood 92: , 1998

Pharmacodynamic Models Fixed effect modelFixed effect model Linear modelLinear model Log-linear modelLog-linear model E max modelE max model Sigmoid E max modelSigmoid E max model Effect = E 0 + S[Drug] Effect = I + SLog([Drug]) Effect = EC 50 + [Drug] H E max [Drug] H H

Sigmoid E max PD Model [Drug] Effect (%) EC 50 H = 0.1 H = 5 H = 2 H = 1 H = 0.5

Theophylline Pharmacodynamics Theophylline [mg/L] FEV 1 (% normal) E max = 63% EC 50 = 10 mg/L Mitenko & Ogilvie NEJM 289:600-3, 1973

Carboplatin PK/PD Carboplatin AUC [µghr/ml] Creatinine Clearance [ml/min] % Decrease Platelet Carboplatin Cl TB [ml/min] Van Echo et al. Semin Oncol 16:1-6, 1989

Carboplatin Adaptive Dosing ADULTS CHILDREN