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Research ArticleArticle

Confidence Assessment of the Simcyp Time-Based Approach and a Static Mathematical Model in Predicting Clinical Drug-Drug Interactions for Mechanism-Based CYP3A Inhibitors

Ying-Hong Wang
Drug Metabolism and Disposition July 2010, 38 (7) 1094-1104; DOI: https://doi.org/10.1124/dmd.110.032177
Ying-Hong Wang
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Abstract

Accurate prediction of the extent of mechanism-based CYP3A inhibition is critical in determining the timing of clinical drug interaction studies in drug development. To evaluate the prediction accuracy of the static and Simcyp time-based approaches, 54 clinical drug interactions involving mechanism-based CYP3A inhibitors were predicted using both methods. The Simcyp time-based approach generated better prediction when 0.03 h−1 was used as the hepatic CYP3A enzyme degradation rate constant (kdeg) value. Of the predictions 87 and 55% had an error less than 2 and 0.5, respectively, relative to the observed values, compared with 57 and 20%, respectively, when the Simcyp default kdeg value of 0.0077 h−1 was used. Accuracy improvement using the kdeg value of 0.03 over 0.0077 h−1 was most evident for trials with observed magnitude of interaction greater than 2-fold; predictions with an error less than 0.5 relative to clinical observations increased from 8 to 48%. For the static approach, 76 and 35% of the predictions had an error less than 2 and 0.5, respectively. Both methods generated good predictions for weak and moderate inhibitors. The prediction accuracy could be affected by our knowledge of disposition of a substrate compound, in vitro inactivation parameter estimates, and the ability of Simcyp to accurately simulate the pharmacokinetics of inhibitors. Nonetheless, both the Simcyp and static approaches are useful tools for assessing the drug-drug interaction potential of a mechanism-based CYP3A inhibitor, especially when human pharmacokinetics of the inhibitor is known and 0.03 h−1 is used as the hepatic CYP3A kdeg value.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.032177.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    PBPK
    physiologically based pharmacokinetics
    SR
    sustained-release formulation
    CV
    coefficient of variation
    AUC
    area under the concentration-time curve
    IR
    immediate-release formulation
    GMFE
    geometric mean-fold error
    RMSE
    root mean square error.

  • Received January 12, 2010.
  • Accepted April 2, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (7)
Drug Metabolism and Disposition
Vol. 38, Issue 7
1 Jul 2010
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Research ArticleArticle

Confidence Assessment of the Simcyp Time-Based Approach and a Static Mathematical Model in Predicting Clinical Drug-Drug Interactions for Mechanism-Based CYP3A Inhibitors

Ying-Hong Wang
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1094-1104; DOI: https://doi.org/10.1124/dmd.110.032177

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Research ArticleArticle

Confidence Assessment of the Simcyp Time-Based Approach and a Static Mathematical Model in Predicting Clinical Drug-Drug Interactions for Mechanism-Based CYP3A Inhibitors

Ying-Hong Wang
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1094-1104; DOI: https://doi.org/10.1124/dmd.110.032177
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