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Research ArticleMinireview

Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification

Jennifer E. Sager, Jingjing Yu, Isabelle Ragueneau-Majlessi and Nina Isoherranen
Drug Metabolism and Disposition November 2015, 43 (11) 1823-1837; DOI: https://doi.org/10.1124/dmd.115.065920
Jennifer E. Sager
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington
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Jingjing Yu
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington
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Isabelle Ragueneau-Majlessi
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington
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Nina Isoherranen
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington
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Abstract

Modeling and simulation of drug disposition has emerged as an important tool in drug development, clinical study design and regulatory review, and the number of physiologically based pharmacokinetic (PBPK) modeling related publications and regulatory submissions have risen dramatically in recent years. However, the extent of use of PBPK modeling by researchers, and the public availability of models has not been systematically evaluated. This review evaluates PBPK-related publications to 1) identify the common applications of PBPK modeling; 2) determine ways in which models are developed; 3) establish how model quality is assessed; and 4) provide a list of publically available PBPK models for sensitive P450 and transporter substrates as well as selective inhibitors and inducers. PubMed searches were conducted using the terms “PBPK” and “physiologically based pharmacokinetic model” to collect published models. Only papers on PBPK modeling of pharmaceutical agents in humans published in English between 2008 and May 2015 were reviewed. A total of 366 PBPK-related articles met the search criteria, with the number of articles published per year rising steadily. Published models were most commonly used for drug-drug interaction predictions (28%), followed by interindividual variability and general clinical pharmacokinetic predictions (23%), formulation or absorption modeling (12%), and predicting age-related changes in pharmacokinetics and disposition (10%). In total, 106 models of sensitive substrates, inhibitors, and inducers were identified. An in-depth analysis of the model development and verification revealed a lack of consistency in model development and quality assessment practices, demonstrating a need for development of best-practice guidelines.

Footnotes

    • Received June 10, 2015.
    • Accepted August 20, 2015.
  • This work was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grant T32-GM007750] and National Institute of Drug Abuse [Grant P01 DA032507].

  • dx.doi.org/10.1124/dmd.115.065920.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (11)
Drug Metabolism and Disposition
Vol. 43, Issue 11
1 Nov 2015
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Research ArticleMinireview

Review of the Use of PBPK Modeling

Jennifer E. Sager, Jingjing Yu, Isabelle Ragueneau-Majlessi and Nina Isoherranen
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1823-1837; DOI: https://doi.org/10.1124/dmd.115.065920

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Research ArticleMinireview

Review of the Use of PBPK Modeling

Jennifer E. Sager, Jingjing Yu, Isabelle Ragueneau-Majlessi and Nina Isoherranen
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1823-1837; DOI: https://doi.org/10.1124/dmd.115.065920
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    • Abstract
    • Introduction
    • Literature Search Strategy
    • PBPK Modeling Articles by Year and Application
    • Published Models of FDA and EMA Recommended Substrates, Inhibitors, and Inducers
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