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

Applications, Challenges, and Outlook for PBPK Modeling and Simulation: A Regulatory, Industrial... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Pharmaceutical Research Springer Journals

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

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References (197)

Publisher
Springer Journals
Copyright
Copyright © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2022
ISSN
0724-8741
eISSN
1573-904X
DOI
10.1007/s11095-022-03274-2
Publisher site
See Article on Publisher Site

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.

Journal

Pharmaceutical Research – Springer Journals

Published: Aug 1, 2022

Keywords: absorption; bioavailability; distribution; drug-drug interaction(s); excretion ; metabolism; pharmacokinetics; physiologically based pharmacokinetic (PBPK)

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