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Sorafenib metabolism, transport, and enterohepatic recycling: physiologically based modeling and simulation in mice

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Abstract

Purpose

This study used uncertainty and sensitivity analysis to evaluate a physiologically based pharmacokinetic (PBPK) model of the complex mechanisms of sorafenib and its two main metabolites, sorafenib glucuronide and sorafenib N-oxide in mice.

Methods

A PBPK model for sorafenib and its two main metabolites was developed to explain disposition in mice. It included relevant influx (Oatp) and efflux (Abcc2 and Abcc3) transporters, hepatic metabolic enzymes (CYP3A4 and UGT1A9), and intestinal β-glucuronidase. Parameterization of drug-specific processes was based on in vitro, ex vivo, and in silico data along with plasma and liver pharmacokinetic data from single and multiple transporter knockout mice.

Results

Uncertainty analysis demonstrated that the model structure and parameter values could explain the observed variability in the pharmacokinetic data. Global sensitivity analysis demonstrated the global effects of metabolizing enzymes on sorafenib and metabolite disposition and the local effects of transporters on their respective substrate exposures. In addition, through hypothesis testing, the model supported that the influx transporter Oatp is a weak substrate for sorafenib and a strong substrate for sorafenib glucuronide and that the efflux transporter Abcc2 is not the only transporter affected in the Abcc2 knockout mouse.

Conclusions

Translation of the mouse model to humans for the purpose of explaining exceptionally high human pharmacokinetic variability and its relationship with exposure-dependent dose-limiting toxicities will require delineation of the importance of these processes on disposition.

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Acknowledgments

This work was supported, in part, by the American Lebanese Syrian Associated Charities (ALSAC), USPHS Cancer Center Support Grant 3P30CA021765 (S.D. Baker), and NCI Grants 5R01CA138744 (S.D. Baker)

Author contributions

ANE, EIZ, AV, SDB, JCP wrote the manuscript. ANE, SDB, JCP designed the research. EIZ, AV performed experimental studies. ANE and JCP performed the research and analyzed the data.

Author information

Authors and Affiliations

  1. School of Pharmacy, University of Waterloo, Waterloo, ON, Canada

    Andrea N. Edginton

  2. Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA

    Eric I. Zimmerman, Aksana Vasilyeva, Sharyn D. Baker & John C. Panetta

  3. Division of Pharmaceutics, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    Sharyn D. Baker

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  1. Andrea N. Edginton
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Correspondence to John C. Panetta.

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Edginton, A.N., Zimmerman, E.I., Vasilyeva, A. et al. Sorafenib metabolism, transport, and enterohepatic recycling: physiologically based modeling and simulation in mice. Cancer Chemother Pharmacol 77, 1039–1052 (2016). https://doi.org/10.1007/s00280-016-3018-6

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  • DOI: https://doi.org/10.1007/s00280-016-3018-6

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