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

2. 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

3. 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

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

5. 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

6. 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

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

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

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

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

11. 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

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

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

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

15. Receptor-Mediated Effects % Maximum Effect [Drug]

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

17. 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

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

19. Cumulative Dose-Effect Curve Dose Cumulative % of Subjects

20. Cumulative Dose-Effect Study Dose Level No. of Subjects No. Responding % Response 11000 210110 310330 410550 510770 610880 710990 81010100

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

22. Doxorubicin Cardiotoxicity Total Doxorubicin Dose [mg/m 2 ] Probability of CHF 0 0.20 0.40 0.60 0.80 1.0 02004006008001000 von Hoff et al. Ann Intern Med 91:710-7, 1979

23. 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

24. Antihypertensive Dose-Effect Johnston Pharmacol Ther 55:53-93, 1992 Dose Range [mg] Lowest Effective Dose [mg] Drug Early Studies Present Dose Propranolol160-5000160-32080 Atenolol100-200050-10025 Hydrochlorthiazide50-40025-5012.5 Captopril75-100050-15037.5 Methyldopa500-6000500-3000750

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

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

27. Doxorubicin Dose in Osteosarcoma Dose Intensity (mg/m 2 /wk) % with >90% Necrosis Smith et al. JNCI 83:1460, 1993 0100200 05101520 0 20 40 60 80 100

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

29. Effect Compartment (PK/PD Model)

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

31. 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

32. 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)

33. THE END

35. 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

36. Thiopurine Metabolic Activation

37. 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%

38. Relative Dose Intensity Dose Rate mg/m 2 /wk R.D.I. RegimenDrugsDrugsRegimen Cyclo3501 CAF-1Doxo1511 FU2501 Cyclo1250.36 CAF-2Doxo12.50.830.56 FU1250.50

39. Oral Mercaptopurine MP Dose (mg/m 2 ) MP AUC [µMhr] AUC = Clearance Dose F Balis et al. Blood 92:3569-77, 1998

40. 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

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

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

43. 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

44. Carboplatin Adaptive Dosing ADULTS CHILDREN