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Elucidating the Plasma and Liver Pharmacokinetics of Simeprevir in Special Populations Using Physiologically Based Pharmacokinetic Modelling

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Abstract

The disposition of simeprevir (SMV) in humans is characterised by cytochrome P450 3A4 metabolism and hepatic uptake by organic anion transporting polypeptide 1B1/3 (OATP1B1/3). This study was designed to investigate SMV plasma and liver exposure upon oral administration in subjects infected with hepatitis C virus (HCV), in subjects of Japanese or Chinese origin, subjects with organ impairment and subjects with OATP genetic polymorphisms, using physiologically based pharmacokinetic modelling. Simulations showed that compared with healthy Caucasian subjects, SMV plasma exposure was 2.4-, 1.7-, 2.2- and 2.0-fold higher, respectively, in HCV-infected Caucasian subjects, in healthy Japanese, healthy Chinese and subjects with severe renal impairment. Further simulations showed that compared with HCV-infected Caucasian subjects, SMV plasma exposure was 1.6-fold higher in HCV-infected Japanese subjects. In subjects with OATP1B1 genetic polymorphisms, no noteworthy changes in SMV pharmacokinetics were observed. Simulations suggested that liver concentrations in Caucasians with HCV are 18 times higher than plasma concentrations.

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Acknowledgements

Medical writing assistance was provided by Manoranjenni Chetty of Certara and editorial support was provided by Kimberley Haines of Complete Medical Communications, both funded by Janssen.

Author contributions

MB, MM and S O-M provided scientific input in the clinical studies, analysis of the data and contributed to the writing of the manuscript.

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Authors and Affiliations

  1. Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium

    Jan Snoeys, Mario Monshouwer & Sivi Ouwerkerk-Mahadevan

  2. Janssen Infectious Diseases, Beerse, Belgium

    Maria Beumont

Authors
  1. Jan Snoeys
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  2. Maria Beumont
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  3. Mario Monshouwer
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  4. Sivi Ouwerkerk-Mahadevan
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Correspondence to Jan Snoeys.

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JS, MB, MM and S O-M are employees of Janssen and may own stock options in the company.

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No funding was received for the preparation of the article.

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Snoeys, J., Beumont, M., Monshouwer, M. et al. Elucidating the Plasma and Liver Pharmacokinetics of Simeprevir in Special Populations Using Physiologically Based Pharmacokinetic Modelling. Clin Pharmacokinet 56, 781–792 (2017). https://doi.org/10.1007/s40262-016-0476-2

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