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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‐controlled, 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 AUC0–12 increased by 15% in patients receiving placebo. In everolimus‐treated patients, mean increases in cyclosporine AUC0–12 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 AUC0–12 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.