Long-term pharmacokinetics of the metabolites of everolimus and cyclosporine in renal transplant recipients

TypeofStudy:An open, phase I, pilot study assessing the long-term changes in the pharmacokinetics of Certican and cyclosporine (CyA) metabolites during combination therapy in renal transplant recipients. Indications:Graft rejection prophylaxis in 3 patients undergoing renal transplantation. Patients:3 patients (mean age 60.3 years). DosageDuration:5 mg once daily in tablet formulation for 4 weeks. Results:Steady state of Certican exposure was reached after 4 to 6 days. AUC0-24h of Certican on day 1 was significantly lower (257 mcg/h/L) than those on day 15 (396 mcg/h/L). On day 1, the Cmax of Certican was significantly lower than on days 15 or day 21. The mean tmax of Certican was 1.2 hours. On day 21, tmax was reached after an average of 0.6 hours. 4 metabolites of Certican were detected in patient blood: hydroxy-everolimus, dihydroxy-everolimus, desmethyl-everolimus, and ring-opened everolimus. On average, the AUC0-24h of hydroxy-everolimus was 70% of the Certican AUC0-24h. The mean AUC0-24h values of the other metabolites in comparison to the Certican AUC0-24h were as follows: dihydroxy-everolimus (37%), ring-opened form of everolimus (25%), and desmethyl-everolimus (18%). The AUC0-24h and Cmax of the Certican metabolites increased significantly from days 1 to day 15. tmax of the metabolites was reached earlier on day 21 than on days 1 and 14. At the doses administered, concomitant of Certican did not affect the pharmacokinetics (tmax, Cmax, and AUC0-24h) of CyA or its metabolites hydroxy-cyclosporine and dihydroxy-cyclosporine. AdverseEffects:No adverse events were mentioned. AuthorsConclusions:In combination with CyA, after reaching steady-state, the Cmax and AUC0-24h of RAD [everolimus] and its metabolites remained stable during the observation period. However, the tmax shifted to shorter times even after steady-state was reached. Since tmax and Cmax are surrogate markers for absorption, our data indicate that the absorption rate of RAD significantly increases during the first 2 weeks. The total AUC0-24h of the RAD metabolites exceeded that of RAD and the ratio of metabolites: RAD did not change over time. FreeText:Patients received concomitant CyA (trough levels: 80-120 mcg/L) and prednisolone (7.5 mg). The pharmacokinetics (area under the concentration time curve (AUC0-24h), maximum concentration (Cmax), time to reach the Cmax (tmax)) of Certican, CyA, and their metabolites were assessed on days 1, 15, and 21 using automated high performance liquid chromatography (HPLC)/mass spectrometry (MS) assay.