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Applications of Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation During Regulatory Review

Clinical Pharmacology & Therapeutics · 2010 · Vol. 89(2) · pp. 259–267

Ping Zhao(Center for Drug Evaluation and Research)L Zhang(Center for Drug Evaluation and Research)Joseph A. Grillo(Center for Drug Evaluation and Research)Q. Liu(Center for Drug Evaluation and Research)Julie Bullock(Center for Drug Evaluation and Research)Young‐Jin Moon(Center for Drug Evaluation and Research)Pengfei Song(Center for Drug Evaluation and Research)Satjit Brar(Center for Drug Evaluation and Research)Rajanikanth Madabushi(Center for Drug Evaluation and Research)Ta C. Wu(Center for Drug Evaluation and Research)B Booth(Center for Drug Evaluation and Research)Nam Atiqur Rahman(Center for Drug Evaluation and Research)K S Reynolds(Center for Drug Evaluation and Research)Eva Gil Berglund(Medical Products Agency)L J Lesko(Center for Drug Evaluation and Research)S-M Huang✉(Center for Drug Evaluation and Research)

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Abstract

Physiologically based pharmacokinetic (PBPK) modeling and simulation is a tool that can help predict the pharmacokinetics of drugs in humans and evaluate the effects of intrinsic (e.g., organ dysfunction, age, genetics) and extrinsic (e.g., drug-drug interactions) factors, alone or in combinations, on drug exposure. The use of this tool is increasing at all stages of the drug development process. This report reviews recent instances of the use of PBPK in decision-making during regulatory review. The examples are based on Center for Drug Evaluation and Research reviews of several submissions for investigational new drugs (INDs) and new drug applications (NDAs) received between July 2008 and June 2010. The use of PBPK modeling and simulation facilitated the following types of decisions: the need to conduct specific clinical pharmacology studies, specific study designs, and appropriate labeling language. The report also discusses the challenges encountered when PBPK modeling and simulation were used in these cases and recommends approaches to facilitating full utilization of this tool.

Pharmacogenetics and Drug Metabolism Statistical Methods in Clinical Trials Pharmaceutical studies and practicesPhysiologically based pharmacokinetic modellingPharmacokineticsDrugClinical pharmacologyPharmacologyComputer scienceComputational biologyMedicineManagement scienceMedical physics

MeSH terms

Computer SimulationDrug and Narcotic ControlHumansModels, BiologicalPharmacokineticsPhysiologyUnited StatesUnited States Food and Drug AdministrationDrug ApprovalInvestigational New Drug Application