In:
The Journal of Clinical Pharmacology, Wiley, Vol. 55, No. 4 ( 2015-04), p. 467-477
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.
Type of Medium:
Online Resource
ISSN:
0091-2700
,
1552-4604
Language:
English
Publisher:
Wiley
Publication Date:
2015
detail.hit.zdb_id:
2010253-7
SSG:
15,3