Biopharmaceutics Applications of Physiologically Based Pharmacokinetic Absorption Modeling and Simulation in Regulatory Submissions to the U.S. Food and Drug Administration for New Drugs

Fang Wu; Heta Shah; Min Li; Peng Duan; Ping Zhao; Sandra Suarez; Kimberly Raines; Yang Zhao; Meng Wang; Ho-Pi Lin; John Duan; Lawrence Yu; Paul Seo

doi:10.1208/s12248-021-00564-2

Biopharmaceutics Applications of Physiologically Based Pharmacokinetic Absorption Modeling and Simulation in Regulatory Submissions to the U.S. Food and Drug Administration for New Drugs

AAPS J. 2021 Feb 22;23(2):31. doi: 10.1208/s12248-021-00564-2.

Authors

Fang Wu^{1

2}, Heta Shah³, Min Li⁴, Peng Duan³, Ping Zhao^{5

6}, Sandra Suarez³, Kimberly Raines⁴, Yang Zhao^{4

5}, Meng Wang^{4

7}, Ho-Pi Lin⁴, John Duan³, Lawrence Yu⁸, Paul Seo⁹

Affiliations

¹ Division of Biopharmaceutics, Office of New Drug Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA. [email protected].
² Division of Quantitative Methods and Modeling, Office of Research and Standard, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA. [email protected].
³ Division of Biopharmaceutics, Office of New Drug Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, 20993, USA.
⁴ Division of Biopharmaceutics, Office of New Drug Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA.
⁵ Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, 20993, USA.
⁶ Bill & Melinda Gates Foundation, Seattle, Washington, 98109, USA.
⁷ Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, 20993, USA.
⁸ Office of New Drug Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, 20993, USA.
⁹ Division of Biopharmaceutics, Office of New Drug Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA. [email protected].

PMID: 33619657
DOI: 10.1208/s12248-021-00564-2

Abstract

Physiologically based pharmacokinetic (PBPK) absorption modeling and simulation is increasingly used as a tool in drug product development, not only in support of clinical pharmacology applications (e.g., drug-drug interaction, dose selection) but also from quality perspective, enhancing drug product understanding. This report provides a summary of the status and the application of PBPK absorption modeling and simulation in new drug application (NDA) submissions to the U.S. Food and Drug Administration to support drug product quality (e.g., clinically relevant dissolution specifications, active pharmaceutical ingredient (API) particle size distribution specifications). During the 10 years from 2008 to 2018, a total of 24 NDA submissions included the use of PBPK absorption modeling and simulations for biopharmaceutics-related assessment. In these submissions, PBPK absorption modeling and simulation served as an impactful tool in establishing the relationship of critical quality attributes (CQAs) including formulation variables, specifically in vitro dissolution, to the in vivo performance. This article also summarizes common practices in PBPK approaches and proposes future directions for the use of PBPK absorption modeling and simulation in drug product quality assessment.Graphical abstract.

Keywords: biopharmaceutics; clinically relevant drug product specifications (CRDPS); dissolution; physiologically based pharmacokinetics (PBPK); quality risk assessment.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Chemistry, Pharmaceutical / standards
Computer Simulation / standards
Drug Approval*
Drug Development / methods*
Drug Development / standards
Drug Liberation / physiology
Gastrointestinal Absorption / physiology*
Humans
Metabolic Clearance Rate / physiology
Models, Biological*
Tissue Distribution / physiology
United States
United States Food and Drug Administration / standards*