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

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Abstract

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.

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Acknowledgements and Disclosures

The authors have no conflict of interest and competing interests to declare for submission entitled "Applications, challenges, and outlook for PBPK modeling and simulation: A regulatory, industrial and academic perspective.

Funding

Part of the work was supported by UWRAPT funded by Gilead Sciences, Amgen, Janssen Pharmaceuticals and Takeda Pharmaceutical Company.

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Authors and Affiliations

  1. Clinical Pharmacology & Pharmacometrics, Janssen Research and Development, Raritan, New Jersey, 08869, USA

    Wen Lin

  2. Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., CA, South San Francisco, USA

    Yuan Chen

  3. Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, 98195, USA

    Jashvant D. Unadkat

  4. Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Room 2128, Silver Spring, Maryland, 20993, USA

    Xinyuan Zhang

  5. Pharmaceutical Sciences, MRL, Merck & Co., Inc., NJ, 07065, Rahway, USA

    Di Wu & Tycho Heimbach

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  1. Wen Lin
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Correspondence to Xinyuan Zhang.

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Lin, W., Chen, Y., Unadkat, J.D. et al. Applications, Challenges, and Outlook for PBPK Modeling and Simulation: A Regulatory, Industrial and Academic Perspective. Pharm Res 39, 1701–1731 (2022). https://doi.org/10.1007/s11095-022-03274-2

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