Bayes PK Models and Applications to Drug Interaction Simulations幻灯片.pptVIP

Bayes PK Models and Applications to Drug Interaction Simulations Lang Li Associate Professor Division of Biostatistics/Clinical Pharmacology School of Medicine Indiana University What is a drug-drug interaction? Drug-drug interaction (DDI) is usually referred as one drug’s pharmacokinetics (absorption, distribution, elimination, or its effect) is affected by the existence of another drug. DDI: Substrate and Inducer/Inhibitor Possible reasons of a DDI: (1) plasma and/or tissue binding (2) carrier-mediated transport across plasma membranes (3) metabolism Rowland and Toner (1997) Clinical Pharmacokinetics Ito et al. (1998) Pharmacy. Review A Midazolam/Ketoconazole Interaction Example Statistical Literature Review (Nonlinear Models) Likelihood based parametric approach: Beal and Sheiner, 1982; Steimer et al. 1987 and Lindstrom and Bates 1992. Likelihood based nonparametric or semi-parametric approach: Mallet et. al. 1988, Davidian and Gallant 1993, Li et al. 2002. Likelihood based parametric model with measurement error, Higgins and Davidian 1998, and Li et al. 2004. Bayesian approach: Wakefield et al. 1996, 1997, 2000; Muller and Rosner 1998, 2002; Gelman et al. 1996. Nonlinear models for subject-specific level data. Drug Interaction Model Development Literature Data Extraction (Data Mining)- A Midazolam (MDZ) Example Result Comparison with DiDB (number of numerical data in abstracts) Drug Interaction Model Development Initial Drug Interaction PK Model - A Midazolam/Ketoconazole Example Published Ketoconazole Data Sets (sample mean profiles) Published MDZ Data Sets (sample mean profiles) Bayes Meta Analysis on Sample Mean Data MCMC vs Stochastic-EM (SEM) DDI Prediction Drug Interaction Model Development A DDI Prediction Assessment Proposal Probabilistic Rule Pr [AUCR in (-inf, 1.25)] 0.90 clinical insignificant inhibition Pr [AUCR in (2.00, inf)] 0.90 clinical significant inhibition Otherwise inconclusive Population-Average vs Subject-