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

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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.

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Disclaimer

Dr. Ping Zhao participated this work while he was an employee at US FDA. The findings and conclusions contained within are those of the authors and do not necessarily reflect the official positions or policies of the Bill & Melinda Gates Foundation.

Funding

The project is partially supported by FDA MCMi funded Oak Ridge Institute for Science and Education (ORISE) Fellowships. The authors thank Drs Da Xu and Huong Moldthan on collecting some parts of the PBPK data included in regulatory submissions. Drs Da Xu and Huong Moldthan were supported by an appointment to the Research Participation Program at CDER, administered by ORISE through an interagency agreement between the US Department of Energy and the FDA.

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Author notes

  1. Fang Wu

    Present address: 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

  2. Ping Zhao

    Present address: Bill & Melinda Gates Foundation, Seattle, Washington, 98109, USA

  3. Yang Zhao

    Present address: 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

  4. Meng Wang

    Present address: Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, 20993, USA

Authors and 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

    Fang Wu, Min Li, Kimberly Raines, Yang Zhao, Meng Wang, Ho-pi Lin & Paul Seo

  2. 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

    Heta Shah, Peng Duan, Sandra Suarez & John Duan

  3. 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

    Ping Zhao

  4. 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

    Lawrence Yu

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  1. Fang Wu
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Wu, F., Shah, H., Li, M. et al. 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 23, 31 (2021). https://doi.org/10.1208/s12248-021-00564-2

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