ment had similar SCH534128 exposure as subjects with normal hepatic function. A similar magnitude of effect is anticipated for boceprevir. No dosage adjustment of VICTRELIS is recommended for patients with hepatic impairment [see Use in Specific Populations (8.7)]. See peginterferon alfa Package Insert for contraindication in patients with hepatic decompensation.
Renal Impairment
The pharmacokinetics of boceprevir was studied in non-HCV-infected subjects with end-stage renal disease (ESRD) requiring hemodialysis following a single 800 mg dose of VICTRELIS. The mean AUC of boceprevir was 10% lower in subjects with ESRD requiring hemodialysis relative to subjects with normal renal function. Hemodialysis removed less than 1% of the boceprevir dose. No dosage adjustment of VICTRELIS is required in patients with any degree of renal impairment.
Gender
Population pharmacokinetic analysis of VICTRELIS indicated that gender had no apparent effect on exposure.
Race
Population pharmacokinetic analysis of VICTRELIS indicated that race had no apparent effect on exposure.
Age
Population pharmacokinetic analysis of VICTRELIS showed that boceprevir exposure was not different across subjects 19 to 65 years old.
12.4 Microbiology
Mechanism of Action
Boceprevir is an inhibitor of the HCV NS3/4A protease that is necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS4A, NS4B, NS5A and NS5B proteins. Boceprevir covalently, yet reversibly, binds to the NS3 protease active site serine (S139) through an (alpha)-ketoamide functional group to inhibit viral replication in HCV-infected host cells. In a biochemical assay, boceprevir inhibited the activity of recombinant HCV genotype 1a and 1b NS3/4A protease enzymes, with Ki values of 14 nM for each subtype.
Activity in Cell Culture
The EC50 and EC90 values for boceprevir against an HCV replicon constructed from a single genotype 1b isolate were approximately 200 nM and 400 nM, respectively, in a 72-hour cell culture assay. Boceprevir cell culture anti-HCV activity was approximately 2-fold lower for an HCV replicon derived from a single genotype 1a isolate, relative to the 1b isolate-derived replicon. In replicon assays, boceprevir had approximately 2-fold reduced activity against a genotype 2a isolate relative to genotype 1a and 1b replicon isolates. In a biochemical assay, boceprevir had approximately 3- and 2-fold reduced activity against NS3/4A proteases derived from single isolates representative of HCV genotypes 2 and 3a, respectively, relative to a genotype 1b-derived NS3/4A protease. The presence of 50% human serum reduced the cell culture anti-HCV activity of boceprevir by approximately 3-fold.
eva luation of varying combinations of boceprevir and interferon alfa-2b that produced 90% suppression of replicon RNA in cell culture showed additivity of effect without evidence of antagonism.
Resistance
In Cell Culture
Resistance to boceprevir was characterized in biochemical and HCV genotype 1b replicon assays. The activity of boceprevir against the HCV NS3/4A protease or genotype 1b replicon was reduced (2- to 10- fold) by the following amino acid substitutions in the NS3 protease domain: V36A/I/M, Q41R, F43C/S, T54A/S, V55A/I, R155K/M/Q, V158I, V170A/T and M175L. A greater than 15-fold reduction in boceprevir anti-HCV activity was conferred by the substitutions T54C, R155G/I/T and A156S/T/V. The fold decrease in boceprevi |
