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Application of in vitro-in vivo extrapolation (IVIVE) and physiologically based pharmacokinetic (PBPK) modelling to investigate the impact of the CYP2C8 polymorphism on rosiglitazone exposure

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

To predict the impact of the CYP2C8*3 genotype on rosiglitazone exposure in the absence and presence of trimethoprim.

Methods

Prior in vitro and in vivo information for rosiglitazone and trimethoprim were collated from the literature. Specifically, data on the frequency of the different allelic forms of CYP2C8 and their metabolic activity for rosiglitazone were incorporated into a physiologically-based pharmacokinetic (PBPK) model within the Simcyp Simulator (V11.1) to predict differences in the relative exposure of rosiglitazone according to CYP2C8*3 genotype in a virtual population.

Results

Following multiple doses of 8 mg rosiglitazone, the predicted mean AUC(0–24) was 37 % lower in CYP2C8*3 homozygotes compared with wildtype homozygotes (p <  0.001), which was consistent with the 36 % lower value observed in vivo (p <  0.001) Kirchheiner et al. (Clin Pharmacol Ther 80:657–667, 2006). Predicted median AUC ratios of rosiglitazone in the presence and absence of trimethoprim ranged from 1.35 to 1.66 for ten virtual trials of subjects with the CYP2C8*1/*1 genotype, which included the observed value of 1.42. In subjects with the CYP2C8*1/*3 genotype, the predicted AUC ratios for all trials were higher than the observed value of 1.18 Kirchheiner et al. (Clin Pharmacol Ther 80:657–667, 2006).

Conclusions

Investigating the drug interactions in individuals with rare allelic forms of drug metabolising enzymes is fraught with many practical problems. Current study demonstrates the utility of prior in vitro metabolism data from such allelic forms to predict the relative exposure of a drug as a function of genotype. However, in vitro inhibition data obtained in one allelic variant (e.g. CYP2C8*1) may not be adequate to predict the in vivo interactions in another allele (e.g. CYP2C8*3), since the inhibitory characteristics of perpetrator might be different in each allelic variant in the same way as that of metabolism of the victim drug by such variants of the enzyme.

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Acknowledgments

We thank Mr James Kay for his assistance with the preparation of this manuscript.

Conflict of interest

Simcyp Limited (a Certara company), provides a commercial PBPK–IVIVE simulator for the pharmaceutical industry. ARH and KRY are employees of Simcyp Limited. ARH is currently seconded to Simcyp on a part-time basis from the University of Manchester. The simulator is freely available, after the completion of the relevant workshops, to centres of excellence in pharmacology and pharmacometrics within academic and other not-for-profit institutions for research and teaching purposes.

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Authors and Affiliations

  1. Simcyp Limited, Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK

    Karen Rowland Yeo & Amin Rostami-Hodjegan

  2. Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South, San Francisco, CA, 94080, USA

    Jane R. Kenny

  3. School of Pharmacy and Pharmaceutical Sciences, Faculty of Medical and Human Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK

    Amin Rostami-Hodjegan

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  1. Karen Rowland Yeo
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Correspondence to Karen Rowland Yeo.

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Yeo, K.R., Kenny, J.R. & Rostami-Hodjegan, A. Application of in vitro-in vivo extrapolation (IVIVE) and physiologically based pharmacokinetic (PBPK) modelling to investigate the impact of the CYP2C8 polymorphism on rosiglitazone exposure. Eur J Clin Pharmacol 69, 1311–1320 (2013). https://doi.org/10.1007/s00228-012-1467-3

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