Palpitations have previously been identified as uncommon for tacrolimus and as common for boceprevir (when taken together with PEG-IFNα and ribavirin).6, 16 The PK of coadministered boceprevir and the calcineurin inhibitors have not been studied in liver transplant patients, which is a limitation for

interpretation of these data. The data in the present study were derived from healthy subjects, and the magnitude of the potential interaction between cyclosporine or tacrolimus and boceprevir in liver transplant patients is not known. Blood concentrations of the calcineurin inhibitors in liver transplant patients with recurrence of HCV are subject to a wider range of influences than those in healthy subjects, which in turn could result in greater interpatient

variability. HCV infection itself appears to reduce the dose of cyclosporine or tacrolimus Opaganib mw required to achieve a given blood level, probably because of down-regulation of hepatic CYP3A4, impaired function of hepatic P-gp, or both.17 The effect is reversed when the HCV-associated inflammatory response is eliminated by antiviral therapy.18 In addition, liver function can change with time after transplantation.19 Based on the results from the present study, dose reductions of cyclosporine should be anticipated when administered with boceprevir and should be guided by close monitoring of cyclosporine blood levels and frequent assessments selleckchem of renal function and cyclosporine-related side effects. For tacrolimus, significant dose reduction and prolongation of the dosing interval will be required, along with close monitoring of tacrolimus concentrations and frequent assessments of renal function and tacrolimus-related side effects. Plasma concentrations of other commonly used immunosuppressants such as sirolimus and everolimus may also be increased during coadministration with boceprevir. Thus, close monitoring of immunosuppressant 上海皓元医药股份有限公司 blood levels is recommended here as well. This

situation is comparable to that of HIV-coinfected patients after liver transplantation who require treatment with ritonavir-boosted HIV protease inhibitors concomitantly with cyclosporine or tacrolimus. HIV protease inhibitors (eg, lopinavir, darunavir, atazanavir, and ritonavir) are all potent CYP3A4 inhibitors, and several reports describe dose reductions of up to 99% of the calcineurin inhibitors when coadministered with HIV protease inhibitors, with dosing schedules of less than once weekly to maintain adequate cyclosporine and tacrolimus concentrations, or both.20-22 Similarly, a preliminary report of the use of telaprevir in a small number of recipients after liver transplantation suggests that tacrolimus dose reduction and prolongation of the dosing interval have been generally well tolerated.