Influence of everolimus on steady-state pharmacokinetics of cyclosporine in maintenance renal transplant patients

To investigate possible interactions of the novel immunosuppressant everolimus with cyclosporine, a multicenter, randomized, double-blind, placebo-con trolled, dose-escalating phase I study was performed. Everolimus regimens (0.75-10 mg/d) were administered for,28 days to stable renal allograft recipients receiving the microemulsion form of cyclosporine. Steady-state cyclosporine profiles were assessed at baseline on day 0 (cyclosporine alone) and on day 21 with everolimus on steady state. By day 21, mean dose-normalized cyclosporine AUC(0-12) increased by 15% in patients receiving placebo. In everolimus-treated patients, mean increases in cyclosporine AUC(0-12) ranged from 7% to 43%, which were not significantly different across all dosing cohorts including placebo. Linear regression of everolimus AUC on day 21 versus the increase in cyclosporine AUC(0-12) yielded a slope not significantly different from a horizontal line (P = ns). In conclusion, these results suggest that steady-state everolimus exposure over the wide range assessed in this Study did not affect steady-state cyclosporine pharmacokinetics.