title: Interactions of the hepatitis C virus protease inhibitor faldaprevir with cytochrome P450 enzymes: in vitro and in vivo correlation.
abstract: The potential inhibition of the major human cytochrome P450 (CYP) enzymes by faldaprevir was evaluated both in vitro and in clinical studies (healthy volunteers and hepatitis C virus [HCV] genotype 1-infected patients). In vitro studies indicated that faldaprevir inhibited CYP2B6, CYP2C9, and CYP3A, and was a weak-to-moderate inactivator of CYP3A4. Faldaprevir 240 mg twice daily in healthy volunteers demonstrated moderate inhibition of hepatic and intestinal CYP3A (oral midazolam: 2.96-fold increase in AUC(0-24 h)), weak inhibition of hepatic CYP3A (intravenous midazolam: 1.56-fold increase in AUC(0-24 h)), weak inhibition of CYP2C9 ([S]-warfarin: 1.29-fold increase in AUC(0-120 h)), and had no relevant effects on CYP1A2, CYP2B6, or CYP2D6. Faldaprevir 120 mg once daily in HCV-infected patients demonstrated weak inhibition of hepatic and intestinal CYP3A (oral midazolam: 1.52-fold increase in AUC(0-∞)), and had no relevant effects on CYP2C9 or CYP1A2. In vitro drug-drug interaction predictions based on inhibitor concentration ([I])/inhibition constant (Ki) ratios tended to overestimate clinical effects and a net-effect model provided a more accurate approach. These studies suggest that faldaprevir shows a dose-dependent inhibition of CYP3A and CYP2C9, and does not induce CYP isoforms.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Sabo
authors.forename: Jens
authors.initials: J
authors.lastname: Kort
authors.forename: Charles
authors.initials: C
authors.lastname: Ballow
authors.forename: Angela D M
authors.initials: AD
authors.lastname: Kashuba
authors.forename: Manuel
authors.initials: M
authors.lastname: Haschke
authors.forename: Manuel
authors.initials: M
authors.lastname: Battegay
authors.forename: Birgit
authors.initials: B
authors.lastname: Girlich
authors.forename: Naitee
authors.initials: N
authors.lastname: Ting
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Curtis
authors.initials: C
authors.lastname: Cooper
authors.forename: Drané
authors.initials: D
authors.lastname: O'Brien
authors.forename: Eleanore
authors.initials: E
authors.lastname: Seibert
authors.forename: Tom S
authors.initials: TS
authors.lastname: Chan
authors.forename: Donald
authors.initials: D
authors.lastname: Tweedie
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Li
mesh_terms: D000293:Adolescent; D000328:Adult; D000621:Aminoisobutyric Acids; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D064368:Healthy Volunteers; D006526:Hepatitis C / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects; D008874:Midazolam / Q000493:pharmacokinetics; D008875:Middle Aged; D009842:Oligopeptides / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000494:pharmacology*; D011804:Quinolines; D013844:Thiazoles / Q000494:pharmacology*; D014859:Warfarin / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000621:Aminoisobutyric Acids; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D009842:Oligopeptides; D011480:Protease Inhibitors; D011804:Quinolines; D013844:Thiazoles; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; C552340:faldaprevir; D011392:Proline; D007930:Leucine; D008874:Midazolam
keywords: clinical research (CRE); clinical trials (CTR); drug interactions; infectious diseases (INF); pharmacokinetics and drug metabolism