Differential influence of two cyclosporine formulations on everolimus pharmacokinetics: A clinically relevant pharmacokinetic interaction

Everolimus is an immunosuppressant intended for use with cyclosporine in acute-rejection prophylaxis following organ transplantation. The possibility of a drug interaction of cyclosporine on everolimus was assessed. In this randomized, two-period, crossover Study, 24 healthy subjects received a single oral dose of 2 mg everolimus alone and with one of two cyclosporine formulations: either 175 mg Neoral or 300 mg Sandimmune. The single doses of Neoral and Sandimmune were chosen to yield similar average areas under the concentration-time curve (AUC). Treatments were separated by a 14-day washout period. Cyclosporine AUCs were similar for both formulations (p = 0.53), whereas the peak concentration (C-max) was significantly higher for Neoral (p = 0.02). Simultaneous administration of Neoral with everolimus increased everolimus C-max and AUC by 82% and 168%, respectively (p = 0.0001). Coadministration of Sandimmune with everolimus did not affect everolimus C-max (p = 0.59) but increased everolimus A UC by 74% on average (p = 0.0001). Everolimus elimination half-lives were unchanged in the presence of both cyclosporine formulations. The everolimus A LTC increase with Neoral coadministration was significantly greater than the AUC increase with Sandimmune (p = 0.008). However, there tvas no apparent association between cyclosporine C-max and the change in everolimus AUC with cyclosporine coadministration. If Neoral or Sandimmune is removed from an everolimus-cyclosporine immunosuppressive regimen, a two- to three-fold decrease in everolimus exposure is expected. Therapeutic monitoring of everolimus concentrations would be helpful after the removal of cyclosporine to individually titrate everolimus exposure. (C) 2002 the American College of Clinical Pharmacology.