Asunaprevir (BMS-650032) is a potent hepatitis C virus (HCV) NS3 protease inhibitor for the treatment of hepatitis C virus infection. Asunaprevir competitively binds to the NS3/4A protease complex, with K(i) values of 0.4 and 0.24 nM against recombinant enzymes representing genotypes 1a (H77) and 1b (J4L6S), respectively. In cell culture, asunaprevir (BMS-650032) inhibited replication of HCV replicons representing genotypes 1 and 4, with 50% effective concentrations (EC(50)s) ranging from 1 to 4 nM, and had weaker activity against genotypes 2 and 3 (EC(50), 67 to 1,162 nM). Asunaprevir at doses of 200 to 600 mg resulted in rapid HCV RNA decreases from the baseline; maximal mean changes in HCV RNA over time were 2.7 and 3.5 log(10) IU/ml in the SAD and MAD studies, respectively. Plasma and tissue exposures in vivo in several animal species indicated that asunaprevir displayed a hepatotropic disposition (liver-to-plasma ratios ranging from 40- to 359-fold across species). Asunaprevir (BMS-650032) is currently in phase III clinical trials.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
The effect of hepatic impairment on the pharmacokinetics of asunaprevir, an HCV NS3 protease inhibitor.
Eley T, et al. Antivir Ther. 2014 Apr 7. PMID: 24704773.
The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection.
Scola PM, et al. J Med Chem. 2014 Mar 13;57(5):1730-52. PMID: 24564672.
Preclinical Profile and Characterization of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir (BMS-650032).
McPhee F, et al. Antimicrob Agents Chemother. 2012 Oct;56(10):5387-96. PMID: 22869577.
Resistance analysis of the hepatitis C virus NS3 protease inhibitor asunaprevir.
McPhee F, et al. Antimicrob Agents Chemother. 2012 Jul;56(7):3670-81. PMID: 22508297.
Single- and multiple-ascending-dose studies of the NS3 protease inhibitor asunaprevir in subjects with or without chronic hepatitis C.
Pasquinelli C, et al. Antimicrob Agents Chemother. 2012 Apr;56(4):1838-44. PMID: 22290978.
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