The Effects of Boceprevir and Telaprevir on the Pharmacokinetics of Maraviroc

Abstract

Objective:To evaluate the effects of boceprevir (BOC) and telaprevir (TVR) on the pharmacokinetics (PK) of maraviroc (MVC) in healthy volunteers.Methods:In this open-label, fixed-sequence study, 14 volunteers received MVC 150 mg twice daily alone for 5 days (period 1), followed by MVC + BOC 800 mg 3 times daily and MVC + TVR 750 mg 3 times daily, each for 10 days in periods 2 and 3, respectively, with a ≥10-day wash-out. PK was analyzed on day 5 of period 1 and day 10 of periods 2 and 3. Safety was also assessed.Results:Ratios of the adjusted geometric means (90% confidence intervals) for MVC area under the curve from predose to 12 hours, maximum plasma concentration, and plasma concentration at 12 hours were 3.02 (2.53 to 3.59), 3.33 (2.54 to 4.36), and 2.78 (2.40 to 3.23), respectively, for MVC + BOC versus MVC alone, and 9.49 (7.94 to 11.34), 7.81 (5.92 to 10.32), and 10.17 (8.73 to 11.85), respectively, for MVC + TVR versus MVC alone. PK profiles for MVC + BOC or TVR were consistent with historic values for BOC and TVR monotherapy. Adverse event incidence was higher with MVC + BOC and MVC + TVR versus MVC alone. Dysgeusia (50%) and pruritus (29%) occurred most commonly with MVC + BOC, and fatigue (46%) and headache (31%) with MVC + TVR. There were no serious adverse events.Conclusions:MVC exposures were significantly increased with BOC or TVR, therefore MVC should be dosed at 150 mg twice daily when coadministered with these newly approved hepatitis C protease inhibitors. No dose adjustment for BOC or TVR is warranted with MVC. MVC + BOC or TVR was generally well tolerated with no unexpected safety findings.

Mechanistic Evaluation of the Complex Drug-Drug Interactions of Maraviroc: Contribution of Cytochrome P450 3A, P-Glycoprotein and Organic Anion Transporting Polypeptide 1B1

“…MVC exposure was shown to increase significantly when coadministered with strong CYP3A/P-gp inhibitors in humans (Hyland et al, 2008). Clinical studies have also indicated that the mean area under the plasma concentration-time curve (AUC) of MVC increased by approximately 9.5-fold when treated with telaprevir (TVR) (Vourvahis et al, 2014). The magnitude of this interaction is much greater than that observed with other strong CYP3A probe inhibitors (e.g., 2.5-fold with ritonavir and 5-fold with ketoconazole) (Abel et al, 2008b;Vourvahis et al, 2014).…”

“…Clinical studies have also indicated that the mean area under the plasma concentration-time curve (AUC) of MVC increased by approximately 9.5-fold when treated with telaprevir (TVR) (Vourvahis et al, 2014). The magnitude of this interaction is much greater than that observed with other strong CYP3A probe inhibitors (e.g., 2.5-fold with ritonavir and 5-fold with ketoconazole) (Abel et al, 2008b;Vourvahis et al, 2014). Earlier studies have shown an association between MVC plasma trough concentrations and the SLCO1B1 521TC genotype in patients treated with 60 mg MVC plus etravirine or efavirenz (Siccardi et al, 2010).…”

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

“…The maraviroc geometric mean AUC and C max for maraviroc and boceprevir treatment relative to maraviroc alone were 3.02 (90 % CI 2.53-3.59) and 3.33 (90 % CI 2.54-3.59). In contrast, maraviroc had no significant impact on the pharmacokinetic profile of boceprevir [18]. The authors concluded that maraviroc should be dosed at 150 mg twice daily when coadministered with boceprevir, similar to the recommendations for maraviroc in combination with other potent CYP3A/P-gp inhibitors [18].…”

“…In contrast, maraviroc had no significant impact on the pharmacokinetic profile of boceprevir [18]. The authors concluded that maraviroc should be dosed at 150 mg twice daily when coadministered with boceprevir, similar to the recommendations for maraviroc in combination with other potent CYP3A/P-gp inhibitors [18]. Use of maraviroc has been associated with hepatotoxicity, and therefore should be administered with caution in patients with pre-existing liver dysfunction, or with HCV or hepatitis B-virus coinfection.…”

“…In an openlabel, fixed-sequence study conducted in 14 healthy volunteers, maraviroc exposures were significantly increased with coadministration of boceprevir (Table 2) [18]. The maraviroc geometric mean AUC and C max for maraviroc and boceprevir treatment relative to maraviroc alone were 3.02 (90 % CI 2.53-3.59) and 3.33 (90 % CI 2.54-3.59).…”