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 (Cmax) was significantly higher for Neoral (p = 0.02). Simultaneous administration of Neoral with everolimus increased everolimus Cmax and AUC by 82% and 168%, respectively (p = 0.0001). Coadministration of Sandimmune with everolimus did not affect everolimus Cmax (p = 0.59) but increased everolimus AUC by 74% on average (p = 0.0001). Everolimus elimination half-lives were unchanged in the presence of both cyclosporine formulations. The everolimus AUC increase with Neoral coadministration was significantly greater than the AUC increase with Sandimmune (p = 0.008). However, there was no apparent association between cyclosporine Cmax 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.
Kovarik
John M
JM
Novartis Pharmaceuticals, Basel, Switzerland.
Kalbag
Jyoti
J
Figueiredo
Joaquim
J
Rouilly
Marisel
M
Frazier
O'Bannon Larita
OL
Rordorf
Christiane
C
D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D016001:Confidence Intervals; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000493:pharmacokinetics*; D004347:Drug Interactions / Q000502:physiology; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016018:Least-Squares Analysis; D008297:Male; D020123:Sirolimus / Q000031:analogs & derivatives / Q000493:pharmacokinetics*
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus