1/17/2013. Dose Response and Concentration Response Analysis of Drug Effects
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1 Dose Response and Concentration Response Analysis of Drug Effects Juan J. L. Lertora. M.D., Ph.D. IH Clinical Center January 17, 213 1
2 DOSE-EFFECT RELATIOSHIP The intensity and duration of a drug s effect(s) are a function of the drug dose and drug concentration at the effect site 2
3 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 3
4 Endpoints to Monitor Drug Effect Farnesyltransferase Inhibitors for Cancer LEVEL EDPOIT Molecular Farnesyltransferase inhibition Cellular Proliferation rate, apoptosis Tumor Response (change in tumor size) Organism Survival, quality of life 4
5 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 5
6 Erythropoietin and Anemia 25 2 Peak Hematocrit Increment [%] Eschbach et al. EJM 316:73-8, Erythropoietin Dose [units/kg] 6
7 Drug-Receptor Interactions Drug Drug-Receptor Complex Ligand-binding domain Effector domain Receptor k 1 k 2 Effect Effect = Maximal effect [Drug] K D + [Drug] (K D = k 2 /k 1 ) 7
8 Drug-Receptor Interactions Receptor-Effector system (signal-transduction pathway) G-protein coupled receptors Receptor-enzymes Ion channels uclear receptors 8
9 Dose-Effect Relationship Effect = Maximal effect [Drug] K D + [Drug] Effect = Maximal effect [Drug] K D + [Drug] Effect = Maximal effect if [Drug] >> K D 9
10 Graded Dose-Effect Curve 1 Maximal effect 8 % of Maximal Effect EC 5 [Drug] 1
11 Log Dose-Effect Curve 1 8 % of Maximal Effect EC [Drug] 11
12 Lidocaine Graded Dose-Effect 1 2 Analog Pain Score Ferrante et al. Anesth Analg 82:91-7, Lidocaine Blood Level [µg/ml] 12
13 Theophylline Dose-Effect 1 8 Relaxation % Control 6 4 PDE Inhibition 2 Rabe et al. Eur Respir J 8:637-42, Theophylline [µm] 13
14 Theophylline Pharmacodynamics FEV 1 (% normal) E max = 63% EC 5 = 1 mg/l Mitenko & Ogilvie EJM 289:6-3, Theophylline [mg/l] 14
15 Decrease in FPG from Placebo [mg/dl] 1/17/213 Metformin Dose-Response Decrease in HbA 1c from Placebo [%] Garber et al. Am J Med 12:491-7, Dose [mg/d] 15
16 Dose-Effect Parameters POTECY: The sensitivity of an organ or tissue to the drug EFFICACY: The maximum effect 16
17 Comparing Dose-Effect Curves 1 8 Drug A Drug B % of Maximal Effect 6 4 Drug C 2 Maximal effect [Drug] Effect = K D + [Drug] [Drug] 17
18 Thiopurine Cytotoxicity 1% Thioguanine Cytotoxic Effect 8% 6% 4% H 2 S H Mercaptopurine S H 2% Adamson et al. Leukemia Res 18:85-1, 1994 % Thiopurine [M] 18
19 Thiopurine Metabolic Activation SH MP SH TG 6 6 H H 2 H PRPP PRPP SH SH SH SH HO H 2 H 2 PO 4 CH 2 O PO 4 CH 2 O PO 4 CH 2 O (PO 4 ) 3 CH 2 O HO OH TIMP HO OH TXMP HO OH TGMP HO R (d)tgtp 19
20 Oral Mercaptopurine 5 4 AUC = Dose F Clearance MP AUC [µm hr] Balis et al. Blood 92: , MP Dose (mg/m 2 ) 2
21 Receptor-Mediated Effects 1 Agonist 8 % Maximum Effect Partial agonist Antagonist [Drug] 21
22 Receptor-Mediated Effects Agonist Partial agonist Antagonist Inverse agonist Receptors can exist in at least two conformations: active and inactive. An inverse agonist drives the equilibrium toward the inactive conformation. 22
23 Drug Interactions 1 Agonist 8 Agonist + competitive antagonist % of Maximal Effect 6 4 Agonist + non-competitive antagonist [Drug] 23
24 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 24
25 Quantal Dose-Effect Distribution 5 ED 5 4 # of Subjects Threshold Dose 25
26 Cumulative Dose-Effect Curve 1 8 Cumulative % of Subjects Dose 26
27 Cumulative Dose-Effect Study Dose Level o. of Subjects o. Responding % Response
28 Therapeutic and Toxic Effects 1 8 Therapeutic Toxic % Responding ED 99 ED Dose TD 1 TD 5 Indices 28
29 Therapeutic Indices Therapeutic Ratio = TD 5 ED 5 = 2.5 Certain Safety Factor = TD 1 ED 99 = 1.3 Standard Safety Margin = TD 1 - ED 99 ED 99 X 1 = 31% 29
30 Percent of patients 1/17/213 Digoxin Therapeutic Index Ventricular slowing Vomiting Digoxin (single oral dose, µg/kg) 3
31 Doxorubicin Cardiotoxicity 1..8 Probability of CHF von Hoff et al. Ann Intern Med 91:71-7, Total Doxorubicin Dose [mg/m 2 ] 31
32 Lidocaine Quantal Dose-Effect 1 8 ED 9 = 49 mg % Achieving Complete Analgesia ED 5 = 4 mg Ferrante et al. Anesth Analg 82:91-7, Total Lidocaine Dose (mg) 32
33 Antihypertensive Dose-Effect Dose Range [mg] Drug Early Studies Present Dose Lowest Effective Dose [mg] Propranolol Atenolol Hydrochlorothiazide Captopril Methyldopa Johnston Pharmacol Ther 55:53-93,
34 Antihypertensive Drugs 1 8 Desirable Dose Range Dose Range most often used % with Maximal Effect Adverse Effects Log Dose 34
35 Relating Dose to Effect In Vivo Dose Effect site Concentration Effect Pharmacokinetics Age Absorption Distribution Elimination Drug interactions Pharmacodynamics Tissue/organ sensitivity (receptor status) 35
36 Effect Compartment (PK/PD Model) Peripheral dx p dt k 12 C V c k 21 X p k 21 k 12 dc dt k V c (k 1 k 12 ) C k 21 Xp V c k Central k 1e Effect dc e dt k 1e C V c V e k e C e E(t) E C H max e EC H H 5 C e k 1 k e 36
37 Concentration and Effect vs. Time 1 on-steady State 1 8 Central Compartment 8 Conc./ Amount 6 4 Peripheral Compartment Effect 6 4 Effect [% of E max ] 2 Effect Compartment Time 37
38 Pharmacodynamic Models Fixed effect model Linear model Log-linear model E max model Sigmoid E max model Effect = E + S [Drug] Effect = I + S Log([Drug]) E max [Drug] H Effect = H EC5 + [Drug] H 38
39 Sigmoid E max PD Model Effect (%) Effect (%) H = H = 2 8 H = H =.5 H = EC 5 2 EC [Drug]
40 Hysteresis and Proteresis Loops Intensity of Drug Effect Hysteresis Loop (Counterclockwise) Equilibration delay in plasma and effect site conc. Formation of active metabolite Receptor up-regulation Intensity of Drug Effect Tolerance Proteresis Loop (Clockwise) Receptor tachyphylaxis Plasma Drug Concentration 4
41 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) 41
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