Marc R. Gastonguay, Ph.D. - CDE · METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012 Application of...
Transcript of Marc R. Gastonguay, Ph.D. - CDE · METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012 Application of...
METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Application of Population Pharmacokinetic and Pharmacodynamic Modeling and Simulation Marc R. Gastonguay, Ph.D.
Scientific Director, Metrum Institute [email protected] President & CEO, Metrum Research Group [email protected]
2 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Overview
Ø Population PK-PD in Modeling/Simulation Context
Ø General Types of Applications
Ø Specific Examples ► Dosing in Neonates, Infants and Children ► Understanding Clinical Pharmacology/Drug Metabolism ► Impact of Adherence to Prescribed Dosing Regimen ► Impact of Renal Impairment ► Dose Selection ► Projection of Target Response (Efficacy) ► Projection of Toxicity Response ► Clinical Trial Simulation
Ø Further Considerations
3 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
General Types of Applications of Population PK-PD
Ø Descriptive reflection of population ► Covariate effects ► PK-PD relationship
Ø Dose and dosing regimen selection
Ø Dosing and labeling for special populations Ø Biomarker PK-PD for internal decision-making
► Target attainment ► Translation to clinical outcomes
Ø Disease Progression Ø Simulation of expected response
► Assessment of target profile (efficacy and toxicity) Ø Clinical trial simulation
► Optimize design
4 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Evolution of Modeling/Simulation in Drug Development
1980 1990 2000 2010 2020
Individual Dosing & TDM
Population PK Software
M&S to Explore Patient Dose Regimens
M&S for Trial Design Decision-Making (MMF)
Multiscale Systems Biology/Pharmacology
Methods & Algorithms
FDA PKPD Conferences, NMusers, PAGE, etc.
Trial Sim for Teaching Stats
Sim for Training Pharmacologists
Cloud Computing MC Sim BE Study Designs
Simulation to Explore Labeled Dosing
MBMA of Therapeutic Areas
Probability of Technical Success
Dose-Selection
Adaptive Trial Designs
Comparative Effectiveness Trial Simulation Software
PBPK Simulation: Tox
PBPK Simulation, ADME
5 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
M&S-Based Drug Development Today (?)
Cross-Program M&S Platforms/Activities (Therapeutic Area Model Based Meta-Analysis, Multiscale Systems Models,
Disease Progression Models, Portfolio Lead Optimization)
Trial Simulations to Optimize Ph 2/3 Designs
Bayesian Analysis & Adaptive Designs, Dose Selection
Pop PKPD M&S for Labeling Support
Preclinical & Early Development PK-PD, MTD, Biomarkers
Prob. Technical Success, Proof of Concept
Comparative Effectiveness
Building Knowledge in Drug Development
6 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Understand the Clinical/Development Questions
Should We Invest Further?!
Will this trial succeed?
What’s the target product profile?
Is toxicity a concern at this dose?
7 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Quantitative Decision Criteria
Less than or Equal to 5 mmHg!
Less Than 12% Incidence Rate
effect size of + 3 points no more than 10 msec
8 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
dose (mg/kg)
prob
abilit
y
0.00
0.05
0.10
0 10 20 30
17 % 1 %
Focus M&S to Address Relevant Quantitative Questions
Expected Toxicity Incidence
Given our current state of knowledge… There is a 17% probability of tox. incidence being greater than 12% But.. the probability of an incidence rate greater than 30% is very low.
(Bayesian) model-based probability distribution
10 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Dosing of Fluconazole in Neonates
Wade et al. Pediatr Infect Dis J 2009; 28: 717–723
11 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Dosing of Fluconazole in Neonates
Wade et al. Pediatr Infect Dis J 2009;28: 717–723
12 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Dosing of Fluconazole in Neonates
Wade et al. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Nov. 2008, p. 4043–4049.
13 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Pediatric Tinzaparin Pharmacodynamics
Gastonguay et al. Optimizing a Bayesian dose-adjustment scheme for a pediatric trial: A simulation study. in Simulation for designing clinical trials: A pharmacokinetic-pharmacodynamic modeling perspective. Marcel Dekker, NY, 2003.
14 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Pediatric Tinzaparin Pharmacodynamics
Gastonguay et al. Optimizing a Bayesian dose-adjustment scheme for a pediatric trial: A simulation study. in Simulation for designing clinical trials: A pharmacokinetic-pharmacodynamic modeling perspective. Marcel Dekker, NY, 2003.
Weight based: Dose = AdultDose x weight/70 kg Allometric: Dose = AdultDose x (weight/70 kg)0.75
15 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Dexmedetomidine Pop PK in Infants
Su et al. Anesth Analg 2010;110:1383–92
16 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Pediatric Dosing Rules for Pantoprazole
Knebel et al. J Clin Pharmacol. 2011 Mar;51(3):333-45. Epub 2010 May 19.
17 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Chlorzoxazone Metabolic Ratio and Renal Function
Nolin et al. Clin Pharmacol Ther 2003;74:555-68.
18 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Adherence Effect on Pop PK
Bies et al. Am J Geriatr Psychiatry 2002; 10:696–705
19 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Adherence Effect on Pop PK
Bies et al. Am J Geriatr Psychiatry 2002; 10:696–705
20 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Varenicline PK-PD, Special Populations
Ravva et al. Br J Clin Pharmacol. 2009 Nov;68(5):669-81.
21 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Varenicline PK-PD, Dose Selection
Ravva et al. Clin Pharmacol Ther. 2010 Mar;87(3):336-44. Epub 2010 Jan 27.
22 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Istradefylline Dose Selection in Parkinson’s Disease
Knebel et al. J Clin Pharmacol. 2011 Dec 12. [Epub ahead of print]
23 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
PK-PD of Fc-Osteoprotegrin and Projected Response
Zierhut et al. J Pharmacokinet Pharmacodyn. 2008 Aug;35(4):379-99. Epub 2008 Jul 17.
24 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Tolterodine QTc Prolongation
Sweeney et al. Drug Discoveries & Therapeutics. 2010; 4(1):44-53.
25 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Alzheimer’s Biomarker-Based No-Go Decision - Quantitative target: beta
amyloid response (area above effect curve) defined based on MBMA of published data.
- PD model for biomarker developed from NCE data.
- Posterior probability of achieving target was too low given tox. coverage
- Terminated development
Ruolun Qiu1, Susan Willavize1, Terrence Fullerton1, Marc R. Gastonguay2. Modeling and Simulation of Plasma Aβ in Human After Multiple Oral Doses of PF-3084014, a Potent Gamma Secretase Inhibitor. ACOP, 2009.
26 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Brief History of Published AD Progression Models - Disease progression model published by Holford and Peace1
E[S(t)] = S(0) + α � t + EPBO(t) + EDRUG(Concentration)
- Ito et al2 developed meta-analytic version of this model (based on summary data) and applied it to new data. Ø Inclusion of new covariates (e.g. baseline severity) and modeled
drug effect directly as a function of time and dose
E[S(t)] = S(0) + α � t + EPBO(t) + EDRUG(t, Dose)
- Gillespie et al3 Bayesian Model-Based Meta Analysis Ø Simultaneous modeling of summary-level and patient-level data,
constrains model to capped scale.
1 Holford, N.H. and Peace, K.E. Methodologic aspects of a population pharmacodynamic model for cognitive effects in alzheimer patients treated with tacrine. Proceedings of the National Academy of Sciences of the United States of America 89 (1992):11466–11470. 2 Disease progression meta-analysis model in Alzheimer's disease. Kaori Ito, Sima Ahadieh, Brian Corrigan, Jonathan French, Terence Fullerton, Thomas Tensfeldt, Alzheimer's Disease Working Group Alzheimer's & Dementia: The Journal of the Alzheimer's Association January 2010 (Vol. 6, Issue 1, Pages 39-53) 3 http://metrumrg.com/images/stories/publications/acop2009-adascog.pdf
27 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Disease Progression: ADAScog
Week
Expe
cted
AD
AS−c
og
20
22
24
26
28
30
0 20 40 60 80
Natural ProgressionPlaceboDonepezil 10 mg QD50% DM effect25% DM effect
28 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Fixed Effects Models for Placebo and Symptomatic Drug
29 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
AD Proof of Concept (PoC) Trial Simulation Target product response for change in ADAScog score at 6 months:
• must have -2.5 units • wish for -4 units
30 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Exploring PoC AD Trial Design Options Parallel Cross-Over
31 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Exploring PoC AD Trial Design Options
Given quantitative criteria, explore performance under different assumptions about true drug characteristics.
32 METRUM RESEARCH GROUP & METRUM INSTITUTE, 2012
Summary
- Start with clinical/development questions
- Express decision criteria quantitatively
- Model development is only part of the effort
- Use simulation to explore possible decision paths