Pharmacokinetic Evaluation of the Interaction between Hepatitis C Virus Protease Inhibitor Boceprevir and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Atorvastatin and Pravastatin

Abstract

bBoceprevir is a potent orally administered inhibitor of hepatitis C virus and a strong, reversible inhibitor of CYP3A4, the primary metabolic pathway for many 3-hydroxy-3-methylglutaryl coenzyme A (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 with 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 area under the concentrationtime curve from time zero to infinity after single dosing (AUC inf ) increasing 2.3-fold (90% confidence interval [CI], 1.85, 2.90) and maximum observed concentration in plasma (C max ) 2.7-fold (90% CI, 1.81, 3.90). Pravastatin exposure was slightly increased in the presence of boceprevir, with pravastatin AUC inf increasing 1.63-fold (90% CI, 1.03, 2.58) and C max 1.49-fold (90% CI, 1.03, 2.14). Boceprevir exposure was generally unchanged when the drug was 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. W orldwide, there are an estimated 130 to 170 million individuals infected with hepatitis C virus (1). Comorbidities, such as diabetes and obesity, are more common among patients with hepatitis C virus infection than in the general U.S. population, with as many as 25% of patients with hepatitis C virus infection at risk of comorbid disorders of lipid metabolism (2). Thus, patients with hepatitis C virus infection frequently receive concomitant treatments for hyperlipidemia, including the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors atorvastatin and pravastatin. Understanding potential drug interactions between hepatitis C therapies and HMG-CoA reductase inhibitors is important for optimal treatment of this patient population.Boceprevir is a potent, orally administered ketoamide inhibitor targeting the active site of the hepatitis C virus nonstructural protein 3 (NS3) protease, approved for the treatment of genotype 1 chronic hepatitis C virus infection in adult patients with compensated liver disease (3-6). Addition of boceprevir to a pegylated interferon (peginterferon)-ribavirin backbone is associated with significantly increased rates of sustain...

In Vitro Assessment of Drug-Drug Interaction Potential of Boceprevir Associated with Drug Metabolizing Enzymes and Transporters

“…Therefore, the potential of BOC to inhibit atorvastatin gut metabolism might be an additional contributing factor to the increased systemic exposure of atorvastatin. Also consistent with its moderate inhibitory effect on OATP1B1, BOC has been shown to increase the AUC and C max of pravastatin (40 mg) 1.6-and 1.5-fold, respectively (Hulskotte et al, 2011). In humans, pravastatin is eliminated via hepatobiliary and renal excretion mediated by hepatic OATP/MRP2 and renal OAT3, respectively, with minimal metabolism .…”

“…This finding suggests that BOC should have lesser impact (versus rifampin) on the hepatic elimination of atorvastatin and other dual substrates of OATP1B/CYP3A where uptake is the rate-determining step. Indeed, a recent clinical DDI study showed that BOC increased plasma atorvastatin AUC and C max 2.3-and 2.7-fold, respectively (Hulskotte et al, 2011). It is noteworthy that atorvastatin has low intestinal availability [Fa*fg (intestinal availability) = 0.24] (Shitara, 2011) in humans, conceivably due to gut CYP3A4 metabolism and Pgp efflux (Hochman et al, 2004).…”

Direct acting anti-hepatitis C virus drugs: Clinical pharmacology and future direction

“…Also, Boceprevirmay increase the toxicity of statins via inhibition of OATP1B1 decreasing their hepatic uptake and Simeprevir concentrations may be increased when co-administered with the immunosuppressant cyclosporine due to interaction via transporters. [33,[41][42][43] Because grazoprevir is a substrate of OATP1B1/3, its plasma concentration may be significantly increased by OATP1B1/3 inhibitors (e.g., cyclosporine, lopinavir, saquinavir), and its concurrent use is contraindicated.…”

Clinical Pharmacology Profile of Boceprevir, a Hepatitis C Virus NS3 Protease Inhibitor: Focus on Drug–Drug Interactions

“…and C max GMR for the comparison of atorvastatin plus boceprevir vs. atorvastatin alone indicate a 2.3-and 2.7-fold increase, respectively ( Table 2) [45]. Boceprevir exposure was unchanged when coadministered with atorvastatin, with GMRs of 1.04 and 0.96 for boceprevir C max and AUC 8 (Table 3) [45]. The increased C max and AUC of atorvastatin are consistent with increases in atorvastatin exposure seen with other inhibitors of CYP3A4 metabolism, such as erythromycin and itraconazole [46].…”

“…The AUC ? and C max GMR for the comparison of atorvastatin plus boceprevir vs. atorvastatin alone indicate a 2.3-and 2.7-fold increase, respectively ( Table 2) [45]. Boceprevir exposure was unchanged when coadministered with atorvastatin, with GMRs of 1.04 and 0.96 for boceprevir C max and AUC 8 (Table 3) [45].…”