Applications, Challenges, and Outlook for PBPK Modeling and Simulation: A Regulatory, Industrial and Academic Perspective

Several regulatory guidances on the use of physiologically based pharmacokinetic (PBPK) analyses and physiologically based biopharmaceutics model(s) (PBBM(s)) have been issued. Workshops are routinely held, demonstrating substantial interest in applying these modeling approaches to address scientific questions in drug development. PBPK models and PBBMs have remarkably contributed to model-informed drug development (MIDD) such as anticipating clinical PK outcomes affected by extrinsic and intrinsic factors in general and specific populations. In this review, we proposed practical considerations for a base PBPK model construction and development, summarized current status, challenges including model validation and gaps in system models, and future perspectives in PBPK evaluation to assess a) drug metabolizing enzyme(s)- or drug transporter(s)- mediated drug-drug interactions b) dosing regimen prediction, sampling timepoint selection and dose validation in pediatric patients from newborns to adolescents, c) drug exposure in patients with renal and/or and hepatic organ impairment, d) maternal-fetal drug disposition during pregnancy, and e) pH-mediated drug-drug interactions in patients treated with proton pump inhibitors/acid-reducing agents (PPIs/ARAs) intended for gastric protection. Since PBPK can simulate outcomes in clinical studies with enrollment challenges or ethical issues, the impact of PBPK models on waivers and how to strengthen study waiver is discussed.

Automated summary

This review discusses the applications of physiologically based pharmacokinetic (PBPK) models and physiologically based biopharmaceutics models (PBBMs) in drug development. It proposes practical considerations for constructing and developing base PBPK models and summarizes the current status, challenges, and future perspectives in PBPK evaluation for various scenarios such as drug-drug interactions, pediatric patients, organ impairment, maternal-fetal drug disposition, and pH-mediated drug interactions.