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Research ArticleArticle

Optimization of Drug-Drug Interaction Study Design: Comparison of Minimal Physiologically Based Pharmacokinetic Models on Prediction of CYP3A Inhibition by Ketoconazole

Bing Han, Jialin Mao, Jenny Y. Chien and Stephen D. Hall
Drug Metabolism and Disposition July 2013, 41 (7) 1329-1338; DOI: https://doi.org/10.1124/dmd.112.050732
Bing Han
Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana (B.H., J.M., J.Y.C., S.D.H.); and Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California (J.M.)
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Jialin Mao
Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana (B.H., J.M., J.Y.C., S.D.H.); and Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California (J.M.)
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Jenny Y. Chien
Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana (B.H., J.M., J.Y.C., S.D.H.); and Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California (J.M.)
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Stephen D. Hall
Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana (B.H., J.M., J.Y.C., S.D.H.); and Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California (J.M.)
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Abstract

Ketoconazole is a potent CYP3A inhibitor used to assess the contribution of CYP3A to drug clearance and quantify the increase in drug exposure due to a strong inhibitor. Physiologically based pharmacokinetic (PBPK) models have been used to evaluate treatment regimens resulting in maximal CYP3A inhibition by ketoconazole but have reached different conclusions. We compare two PBPK models of the ketoconazole-midazolam interaction, model 1 (Chien et al., 2006) and model 2 implemented in Simcyp (version 11), to predict 16 published treatment regimens. With use of model 2, 41% of the study point estimates of area under the curve (AUC) ratio and 71% of the 90% confidence intervals were predicted within 1.5-fold of the observed, but these increased to 82 and 100%, respectively, with model 1. For midazolam, model 2 predicted a maximal midazolam AUC ratio of 8 and a hepatic fraction metabolized by CYP3A (fm) of 0.97, whereas model 1 predicted 17 and 0.90, respectively, which are more consistent with observed data. On the basis of model 1, ketoconazole (400 mg QD) for at least 3 days and substrate administration within 2 hours is required for maximal CYP3A inhibition. Ketoconazole treatment regimens that use 200 mg BID underestimate the systemic fraction metabolized by CYP3A (0.86 versus 0.90) for midazolam. The systematic underprediction also applies to CYP3A substrates with high bioavailability and long half-lives. The superior predictive performance of model 1 reflects the need for accumulation of ketoconazole at enzyme site and protracted inhibition. Model 2 is not recommended for inferring optimal study design and estimation of fraction metabolized by CYP3A.

Footnotes

    • Received December 18, 2012.
    • Accepted April 12, 2013.
  • dx.doi.org/10.1124/dmd.112.050732.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (7)
Drug Metabolism and Disposition
Vol. 41, Issue 7
1 Jul 2013
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Research ArticleArticle

Ketoconazole-Midazolam DDI Prediction

Bing Han, Jialin Mao, Jenny Y. Chien and Stephen D. Hall
Drug Metabolism and Disposition July 1, 2013, 41 (7) 1329-1338; DOI: https://doi.org/10.1124/dmd.112.050732

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Research ArticleArticle

Ketoconazole-Midazolam DDI Prediction

Bing Han, Jialin Mao, Jenny Y. Chien and Stephen D. Hall
Drug Metabolism and Disposition July 1, 2013, 41 (7) 1329-1338; DOI: https://doi.org/10.1124/dmd.112.050732
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