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Integrated Use of In Vitro and In Vivo Information for Comprehensive Prediction of Drug Interactions Due to Inhibition of Multiple CYP Isoenzymes

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Abstract

Background

Mechanistic static pharmacokinetic (MSPK) models are simple, have fewer data requirements, and have broader applicability; however, they cannot use in vitro information and cannot distinguish the contributions of multiple cytochrome P450 (CYP) isoenzymes and the hepatic and intestinal first-pass effects appropriately. We aimed to establish a new MSPK analysis framework for the comprehensive prediction of drug interactions (DIs) to overcome these disadvantages.

Methods

Drug interactions that occurred by inhibiting CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A in the liver and CYP3A in the intestine were simultaneously analyzed for 59 substrates and 35 inhibitors. As in vivo information, the observed changes in the area under the concentration-time curve (AUC) and elimination half-life (t1/2), hepatic availability, and urinary excretion ratio were used. As in vitro information, the fraction metabolized (fm) and the inhibition constant (Ki) were used. The contribution ratio (CR) and inhibition ratio (IR) for multiple clearance pathways and hypothetical volume (VHyp) were inferred using the Markov Chain Monte Carlo (MCMC) method.

Result

Using in vivo information from 239 combinations and in vitro 172 fm and 344 Ki values, changes in AUC, and t1/2 were estimated for all 2065 combinations, wherein the AUC was estimated to be more than doubled for 602 combinations. Intake-dependent selective intestinal CYP3A inhibition by grapefruit juice has been suggested. By separating the intestinal contributions, DIs after intravenous dosing were also appropriately inferred.

Conclusion

This framework would be a powerful tool for the reasonable management of various DIs based on all available in vitro and in vivo information.

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Authors and Affiliations

  1. Laboratory of Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan

    Shizuka Hozuki, Hideki Yoshioka, Satoshi Asano, Yukihiro Shibata, Yuta Tamemoto, Hiromi Sato & Akihiro Hisaka

  2. Toxicology and DMPK Research Department, Teijin Pharma Limited, Tokyo, Japan

    Satoshi Asano

  3. Pharmaceutical Science Department, Translational Research Division, Chugai Pharmaceutical Co., LTD., Tokyo, Japan

    Mikiko Nakamura

  4. Laboratory for Safety Assessment and ADME, Asahi Kasei Pharma Corporation, Tokyo, Japan

    Saori Koh

  5. Regulatory Science/Medicinal Safety Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan

    Yukihiro Shibata

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  1. Shizuka Hozuki
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Corresponding author

Correspondence to Akihiro Hisaka.

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Funding

This study was partly supported by AMED under Grant Numbers JP18be0304203, JP19be0304203, JP20be0304203, and JP21be0304203 and supported by the Chiba University SEEDS Fund.

Conflict of interest

The authors have no conflicts of interests.

Availability of data and material

Data necessary for the analysis are attached in the Supplementary Material.

Code availability

Program code necessary for the analysis is attached in the Supplementary Material.

Authors’ contributions

S. Hozuki, H. Sato, and A. Hisaka designed this study. S. Hozuki, S. Asano, M. Nakamura, S. Koh, and A. Hisaka performed this study. S. Hozuki, S. Asano, M. Nakamura, and S. Koh, H. Yoshioka, collected and analyzed the data. S. Hozuki and Y. Shibata and Y. Tamemoto performed the experiment. S. Hozuki, S. Asano, H. Sato and A. Hisaka wrote the manuscript. All authors read and approved the final manuscript.

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Hozuki, S., Yoshioka, H., Asano, S. et al. Integrated Use of In Vitro and In Vivo Information for Comprehensive Prediction of Drug Interactions Due to Inhibition of Multiple CYP Isoenzymes. Clin Pharmacokinet 62, 849–860 (2023). https://doi.org/10.1007/s40262-023-01234-6

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