Pharmacokinetic / pharmacodynamic modeling and simulation in the design and analysis of Randomized Concentration-Controlled Trials (RCCTs)
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1 Pharmacokinetic / pharmacodynamic modeling and simulation in the design and analysis of Randomized Concentration-Controlled Trials (RCCTs) N. Seth Berry, PharmD Senior Scientific Advisor Quantitative Decision Strategies & Analytics Copyright 2015 Quintiles
2 Overview The Causal Chain in Clinical Pharmacology What is a Randomized Concentration-Controlled Trial (RCCT)? How does it differ from a fixed-dose, randomized dose-response controlled trial (RDCT)? What is the difference between Concentration- (C-R) and Dose- (D-R) analyses? What impact does PK variability have on response? High vs. Low PK variability Minimizing Confounding Overlap What is the role of a RCCT in a Drug Development Program? 2
3 Carl Peck, MD The Champion of the Randomized Concentration-Controlled Trial 3
4 The Causal Chain From Dose to Clinical Endpoint Dose Represents the basic amount of drug being administered to a patient Often a static assignment that does not change over time Concentration The amount of drug that is observed in the body Varies within a subject over time due to the effect of absorption, distribution, metabolism, and elimination (ADME) of the drug Additionally can vary between subjects due to differences in the ADME In basic clinical pharmacology receptor theory, the effect the drug has on the body. Varies within a subject over time due to the concentration of drug available to elucidate an effect Additionally can vary between subjects due to differences in the receptors / genetics Is not always quantifiable Clinical Endpoint The observed patient outcome or assessment. Can vary both within and between patients over time. 23 October 2015 Copyright Quintiles 4
5 Population PK Models Nonlinear Mixed Effects Modeling Create Basic Structural Model 1-, 2-, 3-Compartment Route of Administration (Oral, IV) 600 Estimate PK Parameters 500» Volume of Distribution» Clearance Create Error Model Concentration (mg/l)» Absorption Rate Constant Between Subject Variability» Exponential Error Model Within Subject Variability » Proportional Error Model Time After Dose (hr)» Additive Error Model 5 Source: Example developed from analysis of a large, proprietary, de-identified illustrative data set.
6 What is a Randomized Concentration-Controlled Trial (RCCT)? Terminology RDCT (Randomized Dose - Controlled Trial )» Objectives: Dose-; Effectiveness» Design: Randomization to 2+ fixed doses (including placebo) Parallel or cross-over» Analysis: Relationship between the assigned fixed-doses and the observed effect(s) is analyzed RCCT (Randomized Concentration - Controlled Trial)» Objectives: Concentration-; Effectiveness» Design: Randomization to 2+ pre-defined concentration ranges (including zero) Achieved, if necessary, via adaptively individualized doses» Analysis: Relationship between the achieved concentrations and the observed effect(s) is analyzed Concentration Drives Clinical (R)» A Concentration- (C-R) relationship always exists somewhere» Concentration is a confirmed measure of exposure in contrast to uncertain exposure after assigned dosage in a Dose- (D-R) analysis 6
7 Dose- vs Concentration- Design and Analysis Dose- D 1 D 2 R X X D 3 Concentration- O (Placebo) O D 1 D 2 C 1 C 2 C 3 O (Placebo) R X X O C 1 C 2 23 October 2015 Copyright Quintiles 7
8 Implications of Low PK Variability in a RDCT Low PK Variability = No Confounding or Little Overlap 1.0 Dose vs Maximum Concentration (mcg/l) Dose vs Maximum Concentration Dose (mg) Maximum Concentration vs Dose (mg) Maximum Concentration (mcg/l) 23 October 2015 Copyright Quintiles 8
9 Implications of High PK Variability in a RDCT High PK Variability = Confounding Overlap 1.0 Dose vs Maximum Concentration (mcg/l) Dose vs Maximum Concentration Dose (mg) Maximum Concentration vs Dose (mg) Maximum Concentration (mcg/l) 23 October 2015 Copyright Quintiles 9
10 Implications of High PK Variability in a RDCT Confounding Overlap Worse in Narrow Dose Range 1.0 Dose vs Maximum Concentration (mcg/l) Dose vs Maximum Concentration Dose (mg) Maximum Concentration vs Dose (mg) Maximum Concentration (mcg/l) 23 October 2015 Copyright Quintiles 10
11 Concentration- Analysis: The Confounding Effect of High Correlation between PK and RDCT Maximum Concentration vs D 1 D 2 D 3 O (Placebo) RCCT C 1 C 2 C 3 O (Placebo) Maximum Concentration (mcg/l) Maximum Concentration vs Maximum Concentration (mcg/l) A RCCT Protects Against the Disease and Pharmacokinetic Confounders That Cause the Down Bias 11 11
12 Consequences of High PK Variability and/or PK-R Correlation in D-R & C-R Analyses RDCT: valid D-R analysis may be biased by High PK variability» Reduces power unless fixed doses are far apart High correlation between PK and R» May downwards bias D-R relationship unless covariate analysis is employed RDCT: valid post-hoc C-R analysis relies on Low PK variability» High PK variability reduces power Low correlation between PK and R» High correlation downwards biases C-R relationship RCCT: valid C-R analysis Independent of PK variability» High PK variability is controlled via individualized dosing Resistant to downwards bias due to high correlation between PK and R» Further benefits from covariate modeling 12
13 The Uses of a Randomized Concentration-Controlled Trial Efficient, unbiased estimation of the C-R Relationship 1-3 Establishment of Effectiveness 4-6 of a Drug with Narrow Therapeutic Range, and/or High PK Variability Safe trial of a drug with a narrow therapeutic index w/serious toxicities &/or serious consequences of under-exposure 7-9 Examples: 1. Hale, Michael D, and Russell Reeve. Planning a randomized concentration controlled trial with a binary response (Mycophenylate mofetil). Proceedings of the Biopharmaceutical Section, 1994 Joint Statistical Meetings 2. Reeve, Russell and Michael D Hale. Results and efficiency of Bayesian dose adjustment in a clinical trial with binary endpoint. Proceedings of the Biopharmaceutical Section, 1994 Joint Statistical Meetings 3. Hale, Michael D, et al The pharmacokinetic-pharmacodynamic relationship for mycophenolate mofetil in renal transplant, Clin Pharmaco Ther, 64, pp Fletcher CV, Anderson PL, Kakuda TN, Schacker TW, Henry K, Gross CR, Brundage RC. Concentration-controlled compared with conventional antiretroviral therapy for HIV infection. AIDS Mar 8;16(4): Pledger, GW, et al. Flunarizine for treatment of partial seizures : Results of a concentration-controlled trial. Neurology, Vol. 44, No. 10, , p BHAT β-blocker Study Group. A Randomized Trial of Propranolol in Patients With Acute Myocardial Infarction: I. Mortality Results. JAMA. 1982;247(12): Vozeh S, Kewitz G, Perruchoud A, Tschan M, Kopp C, Heitz M, Follath F. Theophylline serum concentration and therapeutic effect in severe acute bronchial obstruction: the optimal use of intravenously administered aminophylline. Rev Respir Dis Feb;125(2): Bever, CT, et al. The effects of 4 aminopyridine in multiple sclerosis patients: Results of a randomized, placebo controlled, double blind, concentration controlled, crossover trial. Neurology June 1994; 44(6): Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui C-H. Conventional versus individualized chemotherapy for childhood acute lymphoblastic leukemia. New Engl J Med 1998; 21: , 13
14 Randomized Concentration-Controlled Trials in Drug Development When Should a RCCT be Considered? Usually in Phase I/II» To Define the Therapeutic Range / Therapeutic Index Concentration Effect Reduction Relationship Concentration Adverse Reaction Frequency/Severity Relationship» To Undertake a Safe Trial (if ADR = severe) In Phase III (rarely)» If Therapeutic Drug Monitoring (TDM) is Contemplated» If Dose Adjustment is the Only Way to Achieve Safe and effective Exposures in the Effective Range» If C-R information is required by a regulatory agency which is concerned about high PK variability or safety When Should a RCCT NOT be Applied? Wide Therapeutic Range Low Inter-individual PK Variability Very Large PD Variability No correlation between PK and Clinical 14
15 Randomized Concentration-Controlled Trials in Drug Development Other Factors Demanding Design Complex Dose-Concentration Titration Procedures Blinding / Drug Packaging Drug Product / Dosage Forms More Costly, Possibly Longer Trial Opportunities Mobile web applications to help guide PK concentration assignments via Bayesian dosing adjustments Large molecules with narrow therapeutic windows Labeling Could Lead to a Requirement for Concentration Monitoring (Therapeutic Drug Monitoring) 15
16 Questions? 16
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