Influence of Everolimus on Steady‐State Pharmacokinetics of Cyclosporine in Maintenance Renal Transplant Patients

Abstract

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.

Therapeutic drug monitoring of cyclosporine and area under the curve prediction using a single time point strategy: appraisal using peak concentration data

“…Table provides the tabulation of the reported C max and AUC values from the various patient studies and healthy subject clinical pharmacology studies reported in the literature . The prediction of AUC values for cyclosporine was performed using the regression equation: and the appropriate fold differences were computed (Table ).…”

“…It was interesting to note that more subjects had higher C1 blood levels (54%) than C2 blood levels (46%) suggesting that C2 monitoring may result in exposure loss in some patients, if not all . In renal transplant patients who were maintained on a stable cyclosporine dose, it was shown that C2 cyclosporine concentrations (range: 681–1080 ng/ml) were at least 30% lower than the C max value (843–1621 ng/ml) which occurred with a median value of 1 h (range: 1–2 h) across most of the dosing cohorts during the pharmacokinetic evaluation days in the study . Falck et al .…”

Everolimus in Combination with Cyclosporin A as Pre- and Posttransplantation Immunosuppressive Therapy in Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

“…Comparison of CsA levels with its own historic data in which MMF was coadministered to CsA [19] indicate a significant increase in c 2h levels when CsA is combined with RAD001 (P 5 .001), whereas differences between trough levels and AUC did not reach significance. In most clinical studies, pharmacokinetics of CsA appear not to be affected by RAD001 coadministration [18,20,21]. However, Kirchner et al [21] observed a nonsignificant 10% augmentation of CsA AUC after administration of a single, oral dose of RAD001.…”

Sirolimus and everolimus intestinal absorption and interaction with calcineurin inhibitors: a differential effect between cyclosporine and tacrolimus

“…Finally, we did not investigate the potential influence of ImTORs on CsA or TAC transport across Caco‐2 cells. However, several clinical studies previously reported that simultaneous administration of ImTORs with cyclosporine or TAC had no significant influence on the overall pharmacokinetic and blood levels of cyclosporine [13,41–43] or TAC [16].…”