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Pharmacokinetics of the NS3 Protease Inhibitor, Asunaprevir (ASV, BMS‐650032), in Phase I Studies in Subjects With or Without Chronic Hepatitis C
Author(s) -
Eley Timothy,
He Bing,
Huang ShuPang,
Li Wenying,
Pasquinelli Claudio,
Rodrigues A. David,
Grasela Dennis M.,
Bertz Richard J.
Publication year - 2013
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.52
Subject(s) - medicine , pharmacokinetics , ns3 , pharmacology , hepatitis c , protease inhibitor (pharmacology) , hepatitis c virus , gastroenterology , virology , virus , viral load , antiretroviral therapy
Asunaprevir (BMS‐650032, ASV) is a potent, selective hepatitis C virus (HCV) NS3 protease inhibitor in clinical evaluation for chronic hepatitis C treatment. ASV pharmacokinetics were evaluated in four single‐ and multiple‐ascending‐dose studies in healthy subjects or subjects with HCV genotype 1 infection and in human mass balance and food‐effect studies. Median T max was 2–4 hours. Although T ½ was 14–23 hours, oral clearance was high (302–668 L/h at doses ≥100 mg). Steady state was achieved by Day 7. The ASV dose–exposure relationship was disproportionate at doses <200 mg but largely proportional for C max and AUC at clinically relevant doses of 200–600 mg (capsule). Following multiple doses, the accumulation index for AUC [TAU] and C min was lower at doses ≥200 mg, suggestive of possible auto‐induction. ASV exposure increased when administered as a solution (vs. suspension) or with a high‐fat meal; the effect was greater for C max than AUC, suggesting a saturable first‐pass process, the mechanism of which remains to be defined. The apparent complexities of ASV pharmacokinetics will be further explored; nevertheless, data from these studies and antiviral activity in phase 2a/2b studies support further development. Clinical studies are ongoing with ASV in combination with other antivirals.