males and 650 mg/kg in females, and rats were administered doses of up to 125 mg/kg in males and 100 mg/kg in females. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested resulting in boceprevir AUC exposures approximately 2.3- and 6.0-fold higher in males and females, respectively, than those in humans at the recommended dose of 800 mg three times daily. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest doses tested resulting in boceprevir AUC exposures similar to those in humans at the recommended dose of 800 mg three times daily.
Boceprevir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosomal aberration in human peripheral blood lymphocytes and mouse micronucleus assays.
Impairment of Fertility
Use with Ribavirin and Peginterferon alfa: In fertility studies in male animals, ribavirin induced reversible testicular toxicity; while peginterferon alfa may impair fertility in females. Please refer to Package Inserts for ribavirin and peginterferon alfa for additional information.
Boceprevir-induced reversible effects on fertility and early embryonic development in female rats, with no effects observed at a 75 mg/kg dose level. At this dose, boceprevir AUC exposures are approximately 1.3-fold higher than those in humans at the recommended dose of 800 mg three times daily. Decreased fertility was also observed in male rats, most likely as a consequence of testicular degeneration. No testicular degeneration was observed at a 15 mg/kg dose level resulting in boceprevir AUC exposures of less than those in humans at the recommended dose of 800 mg three times daily. Testicular degeneration was not observed in mice or monkeys administered boceprevir for 3 months at doses of up to 900 or 1000 mg/kg, respectively. At these doses, boceprevir AUC exposures are approximately 6.8- and 4.4-fold higher in mice and monkeys, respectively, than those in humans at the recommended dose of 800 mg three times daily. Additionally, limited clinical monitoring has revealed no evidence of testicular toxicity in human subjects.
14 CLINICAL STUDIES
The efficacy of VICTRELIS as a treatment for chronic hepatitis C (genotype 1) infection was assessed in approximately 1500 adult subjects who were previously untreated (SPRINT-2) or who had failed previous peginterferon alfa and ribavirin therapy (RESPOND-2) in Phase 3 clinical studies.
Previously Untreated Subjects
SPRINT-2 was a randomized, double-blind, placebo-controlled study comparing two therapeutic regimens of VICTRELIS 800 mg orally three times daily in combination with PR [PegIntron 1.5 µg/kg/week subcutaneously and weight-based dosing with REBETOL (600–1400 mg/day orally divided twice daily)] to PR alone in adult subjects who had chronic hepatitis C (HCV genotype 1) infection with detectable levels of HCV-RNA and were not previously treated with interferon alfa therapy. Subjects were randomized in a 1:1:1 ratio within two separate cohorts (Cohort 1/non-Black and Cohort 2/Black) and were stratified by HCV genotype (1a or 1b) and by HCV-RNA viral load (≤400,000 IU/mL vs. >400,000 IU/mL) to one of the following three treatment arms:
-
PegIntron + REBETOL for 48 weeks (PR48).
-
PegIntron + REBETOL for four weeks followed by VICTRELIS 800 mg three times daily + PegIntron + REBETOL for 24 weeks. The subjects were
