Longitudinal assessment of everolimus in de novo renal transplant recipients over the first post-transplant year: Pharmacokinetics, exposure-responserelationships, and influence on cyclosporine

Objective: Our objective was to characterize the steady-state pharmacokinet ics of everolimus and cyclosporine (INN, ciclosporin) when coadministered i n de novo kidney allograft recipients during the first year after transplan tation. Methods: This study was a multicenter randomized double-blind study of 101 patients who were randomly assigned 1:1:1 to receive everolimus tablets at doses of 0.5 mg, 1 mg, or 2 mg twice daily with cyclosporine and prednisone . Blood sampling for the pharmacokinetics of everolimus and cyclosporine wa s performed on day 1, on weeks 1, 2, 3, and 4, and on months 2, 3, 6, 9, an d 12. Everolimus dose-proportionality and stability over time were assessed in the context of linear regression and ANOVA models. Everolimus exposure- response relationships between area under the blood concentration-time curv e (AUC) and changes in platelets, leukocytes, and Lipids were explored with the median-effect model. Potential differences in cyclosporine dosing and pharmacokinetics at different levels of everolimus exposure were assessed i n the context of ANOVA. Results: Everolimus steady state was reached on or before day 7, with a med ian 3-fold accumulation of drug exposure compared with that after the first postoperative dose. Both steady-state maximum concentration and AUC were d ose proportional over the full dose range when assessed on day 1, as well a s for the full duration of the study at steady state. There was evidence fo r longitudinal stability in AUC of everolimus during the course of the stud y. The interindividual pharmacokinetic variability for AUC was 85.4% and in traindividual, interoccasion variability was 40.8%. Age (range, 17-69 years ), weight (range, 49-106 kg), and sex (65 men and 36 women) were not signif icant contributors to variability. There was an increasing incidence of tra nsient thrombocytopenia (less than or equal to 100 x 10(9)/L) with increasi ng everolimus AUC (P = .03). Cyclosporine doses, trough concentrations, and AUC exhibited similar temporal patterns during the course of the study reg ardless of the co-administered everolimus dose level (P = .13, .82, and .76 , respectively). Conclusions: Everolimus exhibited dose-proportional, stable exposure during the first post-transplant year. for a 4-fold range of everolimus doses the re were no differential effects on cyclosporine dosing or pharmacokinetics.