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Interactions of the hepatitis C virus protease inhibitor faldaprevir with cytochrome P450 enzymes: In vitro and in vivo correlation
Author(s) -
Sabo John P.,
Kort Jens,
Ballow Charles,
Kashuba Angela D.M.,
Haschke Manuel,
Battegay Manuel,
Girlich Birgit,
Ting Naitee,
Lang Benjamin,
Zhang Wei,
Cooper Curtis,
O'Brien Drané,
Seibert Eleanore,
Chan Tom S.,
Tweedie Donald,
Li Yongmei
Publication year - 2015
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.436
Subject(s) - cyp3a , cyp2c9 , pharmacology , cyp2b6 , midazolam , pharmacokinetics , cyp3a4 , in vivo , cyp2d6 , cyp1a2 , protease inhibitor (pharmacology) , in vitro , chemistry , cytochrome p450 , biology , microsome , enzyme , virology , virus , biochemistry , viral load , microbiology and biotechnology , antiretroviral therapy , sedation
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.