title: Elucidating the Plasma and Liver Pharmacokinetics of Simeprevir in Special Populations Using Physiologically Based Pharmacokinetic Modelling.
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.
authors.affiliation: Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium. JSNOEYS@its.jnj.com.
authors.forename: Jan
authors.identifier: 0000-0003-3420-424X
authors.initials: J
authors.lastname: Snoeys
authors.affiliation: Janssen Infectious Diseases, Beerse, Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: Beumont
authors.affiliation: Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium.
authors.forename: Mario
authors.initials: M
authors.lastname: Monshouwer
authors.affiliation: Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium.
authors.forename: Sivi
authors.initials: S
authors.lastname: Ouwerkerk-Mahadevan
mesh_terms: D000998:Antiviral Agents / Q000097:blood / Q000493:pharmacokinetics*; D044466:Asian People; D006526:Hepatitis C / Q000097:blood / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D027361:Organic Anion Transporters / Q000235:genetics; D011110:Polymorphism, Genetic; D051437:Renal Insufficiency / Q000378:metabolism; D000069616:Simeprevir / Q000097:blood / Q000493:pharmacokinetics*; D044465:White People
chemical_list: D000998:Antiviral Agents; D027361:Organic Anion Transporters; D000069616:Simeprevir