Differential pharmacokinetic interaction of tacrolimus and cyclosporine on everolimus

Objective: We characterized the pharmacokinetics of tacrolimus and everolimus in a combined immunosuppressive regimen. Methods: This was an open-label exploratory trial in eight maintenance renal transplant patients with calcineurin inhibitor intolerance initially receiving mycophenolate mofetil (MMF) and tacrolimus. At enrollment, MMF was discontinued and replaced with everolimus 1.5 mg twice a day in study period 1 (days 1 to 10). In period 2 (day 11 to month 3), tacrolimus dose was reduced by half. Results: At study entry tacrolimus trough level (C0) was 7.9 ± 3.9 ng/mL and area under the curve over a dosing interval (AUC) was 132 ± 56 ng · h/mL. The addition of everolimus in period 1 did not change tacrolimus exposure: C0 8.4 ± 4.0 ng/mL, AUC 134 ± 70 ng · h/mL. Everolimus pharmacokinetics in the presence of tacrolimus in period 1 were: C0 3.3 ± 1.2 ng/mL, Cmax 10.4 ± 5.1 ng/mL, AUC 58 ± 20 ng · h/mL. When compared to pharmacokinetic data from a previous study in 47 renal transplant patients receiving everolimus at the same fixed dose (1.5 mg twice a day) with cyclosporine, everolimus exposure was 2.5-fold higher with cyclosporine relative to the data in this study with tacrolimus. After tacrolimus dose reduction in period 2, there was no clinically relevant change in everolimus exposure: C0 3.0 ± 1.1 ng/mL, Cmax 8.2 ± 1.3 ng/mL, AUC 49 ± 10 ng · h/mL. Conclusions: Tacrolimus appears to have a minimal effect on everolimus blood levels compared with the influence of cyclosporine. The dose of everolimus when combined with tacrolimus needs to be higher than when combined with cyclosporine in order to reach a given everolimus blood level. © 2006 Elsevier Inc. All rights reserved.