The effects of relative timing of sirolimus and cyclosporine microemulsion formulation coadministration on the pharmacokinetics of each agent

Introduction: Sirolimus and cyclosporine (INN, ciclosporin) share the same cytochrome P4503A metabolic pathways, and both drugs are substrates for p-glycoprotein countertransport. These factors most likely affect the bioavailability of both drugs. This study served to examine whether the timing of the administration of cyclosporine and sirolimus might significantly affect the relative bioavailability of one or both of these drugs. Methods: In this randomized crossover trial, 24 stable kidney transplant recipients who were treated after transplant with a combination of sirolimus, cyclosporine, and prednisone for at least 3 months before study initiation, received individualized doses of sirolimus once daily and cyclosporine in the microemulsion formulation twice a day. A total of 20 patients completed the full crossover design. Patients were randomized to one of two dosing schedules: 10 of the patients who completed the study received the morning doses of sirolimus and cyclosporine concomitantly for the first 7 days (schedule I), and from days 8 to 14 the sirolimus dose was administered 4 hours after the morning cyclosporine dose. Ten of the patients received the sirolimus dose 4 hours after the morning cyclosporine dose for the first 7 days (schedule II), and from days 8 to 14 they received concomitant morning doses of cyclosporine and sirolimus. Pharmacokinetic profiles of sirolimus and cyclosporine performed on all patients on days 7, 14, and 15 yielded the area under the concentration-time curve (AUC), peak concentration (C(max)), time to C(max) (t(max)), trough cyclosporine concentration (C(o)), and trough sirolimus concentration (C(o)) values. Results: Sirolimus AUC and sirolimus trough levels were consistently and significantly higher when both cyclosporine and sirolimus were administered concomitantly than when they were administered 4 hours apart, No effect attributable to timing of drug administration could be found on cyclosporine pharmacokinetic parameters. Conclusion: This study shows that the relative timing of administration of cyclosporine and sirolimus significantly affects the blood concentrations of sirolimus.