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Research ArticleCommentary

Clearance Prediction Methodology Needs Fundamental Improvement: Trends Common to Rat and Human Hepatocytes/Microsomes and Implications for Experimental Methodology

F. L. Wood, J. B. Houston and D. Hallifax
Drug Metabolism and Disposition November 2017, 45 (11) 1178-1188; DOI: https://doi.org/10.1124/dmd.117.077040
F. L. Wood
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
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J. B. Houston
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
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D. Hallifax
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
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This article has a correction. Please see:

  • Correction to “Clearance Prediction Methodology Needs Fundamental Improvement: Trends Common to Rat and Human Hepatocytes/Microsomes and Implications for Experimental Methodology” - December 01, 2017

Abstract

Although prediction of clearance using hepatocytes and liver microsomes has long played a decisive role in drug discovery, it is widely acknowledged that reliably accurate prediction is not yet achievable despite the predominance of hepatically cleared drugs. Physiologically mechanistic methodology tends to underpredict clearance by several fold, and empirical correction of this bias is confounded by imprecision across drugs. Understanding the causes of prediction uncertainty has been slow, possibly reflecting poor resolution of variables associated with donor source and experimental methods, particularly for the human situation. It has been reported that among published human hepatocyte predictions there was a tendency for underprediction to increase with increasing in vivo intrinsic clearance, suggesting an inherent limitation using this particular system. This implied an artifactual rate limitation in vitro, although preparative effects on cell stability and performance were not yet resolved from assay design limitations. Here, to resolve these issues further, we present an up-to-date and comprehensive examination of predictions from published rat as well as human studies (where n = 128 and 101 hepatocytes and n = 71 and 83 microsomes, respectively) to assess system performance more independently. We report a clear trend of increasing underprediction with increasing in vivo intrinsic clearance, which is similar both between species and between in vitro systems. Hence, prior concerns arising specifically from human in vitro systems may be unfounded and the focus of investigation in the future should be to minimize the potential in vitro assay limitations common to whole cells and subcellular fractions.

Footnotes

    • Received June 13, 2017.
    • Accepted September 6, 2017.
  • ↵1 Current affiliation: The Institute of Cancer Research, Sutton, United Kingdom.

  • This work was funded by the Centre for Applied Pharmacokinetic Research consortium membership, which included GSK, Janssen, Lilly, and Pfizer.

  • https://doi.org/10.1124/dmd.117.077040.

  • Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 45 (11)
Drug Metabolism and Disposition
Vol. 45, Issue 11
1 Nov 2017
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Research ArticleCommentary

In Vitro Assay Performance for Prediction of Clearance

F. L. Wood, J. B. Houston and D. Hallifax
Drug Metabolism and Disposition November 1, 2017, 45 (11) 1178-1188; DOI: https://doi.org/10.1124/dmd.117.077040

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Research ArticleCommentary

In Vitro Assay Performance for Prediction of Clearance

F. L. Wood, J. B. Houston and D. Hallifax
Drug Metabolism and Disposition November 1, 2017, 45 (11) 1178-1188; DOI: https://doi.org/10.1124/dmd.117.077040
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  • Article
    • Abstract
    • Introduction
    • Data Collation and Analysis
    • Comparison of Human and Rat In Vitro Prediction of Intrinsic Clearance
    • Comparison of Predictions from Fresh and Cryopreserved Human Hepatocytes
    • Relationship between Empirical Scaling Factor and In Vivo Clearance
    • Prediction of In Vivo Clearance of UGT Substrates
    • Prediction of In Vivo Clearance of Acidic, Basic, and Neutral Drugs
    • Assessment of Extent of Underprediction in Relation to fup and BDDCS
    • Current Status of In Vitro Prediction of Clearance
    • Future Prospects to Refine In Vitro Prediction of Clearance
    • Acknowledgments
    • Authorship Contributions
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    • Abbreviations
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