title: Asunaprevir: An HCV Protease Inhibitor With Preferential Liver Distribution.
abstract: Asunaprevir is an inhibitor of the hepatitis C virus (HCV) NS3/4A protease, demonstrating efficacy in clinical studies in patients infected with HCV genotype 1 or 4, with either peginterferon/ribavirin or combinations of direct-acting antivirals. Because of preferential distribution of asunaprevir to the liver via organic anion-transporting polypeptide (OATP)-mediated transport, asunaprevir demonstrates high apparent oral clearance and very low plasma concentrations. Asunaprevir plasma concentrations are markedly increased by single-dose rifampin (an OATP inhibitor) and in subjects with moderate to severe hepatic impairment. In addition, modestly higher plasma concentrations of asunaprevir have been noted in subjects infected with HCV relative to healthy subjects and in Asian subjects relative to whites. At the marketed dose, infrequent hepatic transaminase abnormalities were poorly predicted by plasma concentrations. For a compound with these characteristics, hepatic concentrations may have provided an improved understanding of the in vivo pharmacokinetic and pharmacodynamic data to support decision making during development.
authors.affiliation: Research and Development, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Eley
authors.affiliation: Research and Development, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Tushar
authors.initials: T
authors.lastname: Garimella
authors.affiliation: Research and Development, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Wenying
authors.initials: W
authors.lastname: Li
authors.affiliation: Research and Development, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bertz
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006526:Hepatitis C / Q000097:blood / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D011480:Protease Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000998:Antiviral Agents; D007546:Isoquinolines; D011480:Protease Inhibitors; D013449:Sulfonamides; C571889:asunaprevir
keywords: HCV; asunaprevir; distribution; hepatic; uptake