Merck Sharp & Dohme Corp, Molenstraat 110, 5342 CC Oss, The Netherlands.
Boceprevir is a potent orally administered inhibitor of the hepatitis C virus and a strong, reversible inhibitor of CYP3A4, the primary metabolic pathway for many HMG-CoA reductase inhibitors. Thus, the aim of the present study was to investigate drug-drug interactions between atorvastatin or pravastatin, and boceprevir. We conducted a single-center, open-label, fixed-sequence, one-way crossover study in 20 healthy adult volunteers. Subjects received single-dose atorvastatin (40 mg) or pravastatin (40 mg) on day 1 followed by boceprevir (800 mg three times daily) for 7 to 10 days. Repeat single doses of atorvastatin or pravastatin were administered in the presence of steady-state boceprevir. Atorvastatin exposure increased in the presence of boceprevir, with atorvastatin AUCinf increasing 2.3-fold (90% confidence interval [CI] 1.85, 2.90) and Cmax 2.7-fold (90% CI 1.81, 3.90). Pravastatin exposure was slightly increased in the presence of boceprevir, with pravastatin AUCinf increasing 1.63-fold (90% CI 1.03, 2.58) and Cmax 1.49-fold (90% CI 1.03, 2.14). Boceprevir exposure was generally unchanged when coadministered with atorvastatin or pravastatin. All adverse events were mild and consistent with the known safety profile of boceprevir. The observed 130% increase in AUC of atorvastatin supports the use of the lowest possible effective dose of atorvastatin when coadministered with boceprevir, without exceeding a maximum daily dose of 40 mg. The observed 60% increase in pravastatin AUC with boceprevir coadministration supports the initiation of pravastatin treatment at the recommended dose when coadministered with boceprevir, with close clinical monitoring.