Concomitant boceprevir administration increased the AUCinf and Cmax of cyclosporine by 2.7- and 2.0-fold, respectively. Boceprevir coadministration had a substantial effect on the PK of tacrolimus, with coadministered geometric mean AUCinf and Cmax parameter values approximately 17-fold and 10-fold higher than when tacrolimus was administered alone. Drug interactions Talazoparib also have been

identified between cyclosporine and tacrolimus and telaprevir, another recently approved HCV NS3/4A protease inhibitor.10 Coadministration of telaprevir led to a 4.6- and 1.3-fold increase in the dose-normalized AUCinf and Cmax of cyclosporine and a 70- and 9.3-fold increase in the dose-normalized AUCinf and Cmax of tacrolimus, respectively. Neither tacrolimus

nor cyclosporine had any notable effect on the PK of boceprevir. Boceprevir is metabolized by two pathways: aldo ketoreductase, which leads to (among others) a reduced, inactive metabolite (SCH 629144), and CYP3A4/5.3 Although the Cmax and AUC of boceprevir were essentially unchanged in the presence of cyclosporine compared with boceprevir administration alone, a two-fold increase in the Cmax and AUC of the metabolite SCH 629144 was observed after coadministration of boceprevir and cyclosporine. Because this metabolite is not active against HCV, this increase has no consequences with respect selleckchem to clinical efficacy; however, it is not known whether the increase in metabolite exposure could potentially increase side effects. Because cyclosporine is an inhibitor of several proteins in both the drug-metabolizing enzyme and the uptake/efflux transporter systems, data in the present study do not provide insight into whether the increase in SCH 629144 levels is due to its effect on the enzyme/transporter interplay, resulting in an increase in the formation of SCH 629144, a decrease in the elimination of the metabolite, or a combination of both. The contribution of cyclosporine-based P-gp inhibition on drug interactions could not be assessed in this study, given that

the low cyclosporine dose used did not produce plasma concentrations at the levels predicted to incur clinically meaningful P-gp inhibition (1,000-5,000 上海皓元 ng/mL).13 Furthermore, the potential for tacrolimus to inhibit the metabolism of boceprevir may not have been fully assessed in this study because of the low tacrolimus dose used to allow for a large enough safety margin to accommodate the increased concentrations that were expected upon boceprevir coadministration. Coadministration of boceprevir with cyclosporine or tacrolimus was safe and well tolerated in this group of healthy volunteers. Overall, tolerability was consistent with the known safety profile of boceprevir in healthy subjects14-16 and patients with chronic hepatitis C.1, 2, 16 All AEs were mild, there were no treatment discontinuations due to AEs, and dygeusia was the most frequently reported drug-related AE.