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Research ArticleArticle

Hepatic Clearance Predictions from In Vitro–In Vivo Extrapolation and the Biopharmaceutics Drug Disposition Classification System

Christine M. Bowman and Leslie Z. Benet
Drug Metabolism and Disposition November 2016, 44 (11) 1731-1735; DOI: https://doi.org/10.1124/dmd.116.071514
Christine M. Bowman
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California
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Leslie Z. Benet
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California
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Abstract

Predicting in vivo pharmacokinetic parameters such as clearance from in vitro data is a crucial part of the drug-development process. There is a commonly cited trend that drugs that are highly protein-bound and are substrates for hepatic uptake transporters often yield the worst predictions. Given this information, 11 different data sets using human microsomes and hepatocytes were evaluated to search for trends in accuracy, extent of protein binding, and drug classification based on the Biopharmaceutics Drug Disposition Classification System (BDDCS), which makes predictions about transporter effects. As previously reported, both in vitro systems (microsomes and hepatocytes) gave a large number of inaccurate results, defined as predictions falling more than 2-fold outside of in vivo values. The weighted average of the percentage of inaccuracy was 66.5%. BDDCS class 2 drugs, which are subject to transporter effects in vivo unlike class 1 compounds, had a higher percentage of inaccurate predictions and often had slightly larger bias. However, since the weighted average of the percentage of inaccuracy was still high in both classes (81.9% for class 2 and 62.3% for class 1), it may be currently hard to use BDDCS class to predict potential accuracy. The results of this study emphasize the need for improved in vitro to in vivo extrapolation experimental methods, as using physiologically based scaling is still not accurate, and BDDCS cannot currently help predict accurate results.

Footnotes

    • Received May 11, 2016.
    • Accepted August 11, 2016.
  • C.M.B. was supported by the National Science Foundation Graduate Research Fellowship Program [Grant 1144247].

  • dx.doi.org/10.1124/dmd.116.071514.

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

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (11)
Drug Metabolism and Disposition
Vol. 44, Issue 11
1 Nov 2016
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Research ArticleArticle

Hepatic Clearance Predictions and BDDCS

Christine M. Bowman and Leslie Z. Benet
Drug Metabolism and Disposition November 1, 2016, 44 (11) 1731-1735; DOI: https://doi.org/10.1124/dmd.116.071514

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Research ArticleArticle

Hepatic Clearance Predictions and BDDCS

Christine M. Bowman and Leslie Z. Benet
Drug Metabolism and Disposition November 1, 2016, 44 (11) 1731-1735; DOI: https://doi.org/10.1124/dmd.116.071514
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