Pharmacokinetics of the NS3 Protease Inhibitor, Asunaprevir (ASV, BMS-650032), in Phase I Studies in Subjects With or Without Chronic Hepatitis C.
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 Tmax was 2-4 hours. Although T½ 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 Cmax and AUC at clinically relevant doses of 200-600 mg (capsule). Following multiple doses, the accumulation index for AUC[TAU] and Cmin 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 Cmax 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.
Bristol-Myers Squibb, Research and Development, Hopewell, NJ, USA.
Timothy
T
Eley
Bristol-Myers Squibb, Research and Development, Hopewell, NJ, USA.
Bing
B
He
Bristol-Myers Squibb, Research and Development, Princeton, NJ, USA.
Shu-Pang
SP
Huang
Bristol-Myers Squibb, Research and Development, Princeton, NJ, USA.
Wenying
W
Li
Bristol-Myers Squibb, Research and Development, Hopewell, NJ, USA.
Claudio
C
Pasquinelli
Bristol-Myers Squibb, Research and Development, Princeton, NJ, USA.
A David
AD
Rodrigues
Bristol-Myers Squibb, Research and Development, Hopewell, NJ, USA.|Bristol-Myers Squibb, Research and Development, Princeton, NJ, USA.
Dennis M
DM
Grasela
Bristol-Myers Squibb, Research and Development, Hopewell, NJ, USA.
Richard J
RJ
Bertz
NS3; asunaprevir; hepatitis C virus; pharmacokinetics