Pharmacokinetic interaction between the hepatitis C virus protease inhibitor boceprevir and cyclosporine and tacrolimus in healthy volunteers

Abstract

The hepatitis C virus protease inhibitor boceprevir is a strong inhibitor of cytochrome P450 3A4 and 3A5 (CYP3A4/5). Cyclosporine and tacrolimus are calcineurin inhibitor immunosuppressants used to prevent organ rejection after liver transplantation; both are substrates of CYP3A4. This two-part pharmacokinetic interaction study evaluated boceprevir with cyclosporine (part 1) and tacrolimus (part 2). In part 1, 10 subjects received single-dose cyclosporine (100 mg) on day 1, single-dose boceprevir (800 mg) on day 3, and concomitant cyclosporine/boceprevir on day 4. After washout, subjects received boceprevir (800 mg three times a day) for 7 days plus single-dose cyclosporine (100 mg) on day 6. In part 2A, 12 subjects received single-dose tacrolimus (0.5 mg). After washout, they received boceprevir (800 mg three times a day) for 11 days plus single-dose tacrolimus (0.5 mg) on day 6. In part 2B, 10 subjects received single-dose boceprevir (800 mg) and 24 hours later received boceprevir (800 mg) plus tacrolimus (0.5 mg). Coadministration of boceprevir with cyclosporine/tacrolimus was well tolerated. Concomitant boceprevir increased the area under the concentration-time curve from time 0 to infinity after single dosing (AUC inf ) and maximum observed plasma (or blood) concentration (C max ) of cyclosporine with geometric mean ratios (GMRs) (90% confidence interval [CI]) of 2.7 (2.4-3.1) and 2.0 (1.7-2.4), respectively. Concomitant boceprevir increased the AUC inf and C max of tacrolimus with GMRs (90% CI) of 17 (14-21) and 9.9 (8.0-12), respectively. Neither cyclosporine nor tacrolimus coadministration had a meaningful effect on boceprevir pharmacokinetics. Conclusion: Dose adjustments of cyclosporine should be anticipated when administered with boceprevir, guided by close monitoring of cyclosporine blood concentrations and frequent assessments of renal function and cyclosporine-related side effects. Administration of boceprevir plus tacrolimus requires significant dose reduction and prolongation of the dosing interval for tacrolimus, with close monitoring of tacrolimus blood concentrations and frequent assessments of renal function and tacrolimusrelated side effects. (HEPATOLOGY 2012;56:1622-1630

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

“…However, given the high therapeutic dose of BOC, Pgp/BCRP activity is likely saturated and therefore will not significantly impact the intestinal absorption of BOC. This notion is supported by a recent clinical DDI study (Hulskotte et al, 2012b) that CsA (100 mg), a potent inhibitor of Pgp and BCRP, did not have a meaningful effect on the pharmacokinetics of BOC.…”

“…Admittedly, the fact that the model provided reasonable prediction does not eliminate the possibility of the involvement of a metabolite in the observed clinical DDI between midazolam and BOC. Also, this TDI effect of BOC could conceivably be attributable in part to the increased AUC of CsA (2.7-fold) and tacrolimus (17-fold) in humans when coadministered with BOC, as both are substrates of CYP3A (Hulskotte et al, 2012b).…”

Effect of telaprevir on the pharmacokinetics of sirolimus in liver transplant recipients

“…3 Boceprevir increases the DN AUC of cyclosporine 2.7-fold and the DN AUC of tacrolimus 17-fold. 4 Mammalian target of rapamycin inhibitors such as sirolimus and everolimus are increasingly being used after liver transplantation to help preserve renal function. 5 We report here the pharmacokinetics of sirolimus during telaprevir administration.…”

Boceprevir-based triple therapy for belgian liver transplant patients infected with hepatitis C virus: A preliminary experience

“…Boceprevir with a calcineurin inhibitor (CNI) seems to require a lower dose reduction than telaprevir. 3 Here we report the Belgian experience with boceprevir-based triple therapy after liver transplantation. The safety and efficacy of boceprevir treatment in combination with pegylated interferon and ribavirin were investigated in 7 liver transplant patients with recurrent HCV genotype 1 (3 men and 4 women with a mean age of 53 6 10.4 years).…”