463 PHARMACOKINETIC INTERACTIONS BETWEEN THE HCV PROTEASE INHIBITOR BOCEPREVIR AND SIROLIMUS IN HEALTHY SUBJECTS

Abstract

Background and Aims: Boceprevir is a potent, orally administered, ketoamide inhibitor of the hepatitis C virus (HCV) NS3 protease. HCV-related end-stage liver disease and hepatocellular carcinoma are frequent causes of liver transplantation. Sirolimus is a macrolide immunosuppressant frequently used for the prophylaxis of transplant rejection. This study was conducted to evaluate the pharmacokinetic interaction of boceprevir and sirolimus in healthy volunteers. Methods: In this open-label, 3-period, fixed-sequence trial, 12 subjects received single-dose sirolimus (2mg) in period 1 and boceprevir (800mg TID for 6 days) in period 2 with an intervening washout of 14 days. Period 3 immediately followed period 2 with no intervening washout: subjects received sirolimus (2mg SD) plus boceprevir (800mg TID) on day 1 and boceprevir (800mg TID) thereafter for 9 days. Blood samples were collected for the pharmacokinetic assessment of sirolimus and boceprevir. Safety assessments included electrocardiograms, vital signs, clinical laboratory tests, physical examination, and adverse event monitoring. Results: Twelve healthy volunteers were enrolled and 11 completed the trial. Coadministration of boceprevir and sirolimus was well tolerated. Boceprevir co-administration increased the geometric mean AUC0–∞ and Cmax of sirolimus by 8.1-fold and 4.8-fold, respectively, with the corresponding 90% CIs of (7.08, 9.32) for AUC0–∞ and (3.99, 5.88) for Cmax. The elimination half-life of sirolimus increased from 82.5 h to 98.3 h, and the apparent clearance decreased from 9.62 L/min to 1.18 L/min, respectively, with boceprevir coadministration. Sirolimus co-administration did not affect the pharmacokinetics of boceprevir (AUC0–8h and Cmax GMR [90%CI] of 1.0 [0.89, 1.01] and 0.9 [0.82, 1.07], respectively). Conclusions: Concomitant administration of boceprevir and sirolimus resulted in increased steady-state exposures of sirolimus in healthy subjects. The magnitude of the potential interaction between sirolimus and boceprevir in organ transplant patients is not known, but could potentially be higher and more variable than that seen in healthy volunteers. Dose adjustment of sirolimus and/or prolongation of the dosing interval should be anticipated when administered with boceprevir, and should be guided by close monitoring of sirolimus blood concentrations, and frequent assessment of renal function and sirolimus-related side effects.