title: Mechanistic understanding of the nonlinear pharmacokinetics and intersubject variability of simeprevir: A PBPK-guided drug development approach.
abstract: Simeprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, displays nonlinear pharmacokinetics (PK) at therapeutic doses. Using physiologically based PK modeling, various drug-drug interactions were simulated with simeprevir as victim drug to identify whether saturation of the predominant metabolic enzyme (CYP3A4) or the active hepatic transporters (organic anion-transporting polypeptide (OATP)1B1/3) could account for the nonlinear PK. Interactions with ritonavir, a strong CYP3A4 inhibitor that does not affect OATP (at 100 mg dose), erythromycin, a moderate CYP3A4 inhibitor, and efavirenz, a moderate CYP3A inducer that does not affect OATP, demonstrated the involvement of CYP3A4. Interaction studies with low-dose cyclosporine confirmed the role of OATP. The interplay between hepatic uptake and CYP3A4 metabolism was verified by simulations with rifampicin, a potent CYP3A4 inducer and OATP1B1/3 inhibitor, and maintenance doses of cyclosporine. Saturation of gut and liver metabolism by CYP3A4, and saturation of hepatic uptake by OATP1B1/3, seem to account for the observed nonlinear PK of simeprevir.
authors.affiliation: Janssen Research and Development, Beerse, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Snoeys
authors.affiliation: Janssen Research and Development, Beerse, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Beumont
authors.affiliation: Janssen Research and Development, Beerse, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Monshouwer
authors.affiliation: Janssen Research and Development, Beerse, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Ouwerkerk-Mahadevan
mesh_terms: D000480:Alkynes; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000494:pharmacology; D003521:Cyclopropanes; D016572:Cyclosporine / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D004917:Erythromycin / Q000494:pharmacology; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D017711:Nonlinear Dynamics; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology; D019438:Ritonavir / Q000494:pharmacology; D000069616:Simeprevir / Q000493:pharmacokinetics*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000480:Alkynes; D000998:Antiviral Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; D004791:Enzyme Inhibitors; D004917:Erythromycin; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D012293:Rifampin; D019438:Ritonavir; D000069616:Simeprevir; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C503999:SLCO1B1 protein, human; C098320:efavirenz