The pharmacokinetics of everolimus in de novo kidney transplant patients receiving tacrolimus: an analysis from the randomized ASSET study.

Abstract

Pharmacokinetic data regarding a drug-drug interaction between everolimus and tacrolimus are sparse. In a pharmacokinetic substudy of the randomized ASSET trial, 46 de novo kidney transplant patients receiving very low (1.5-3 ng/mL) or low (4-7 ng/mL) tacrolimus exposure after month 3, both with everolimus and steroids, provided area under the curve (AUC) concentration profiles at day 5 and months 1, 3, and 12. At month 12, mean values for tacrolimus trough concentration (C0), peak concentration (Cmax), and AUC0-12 in the very low tacrolimus group were approximately half that in the low tacrolimus group, but everolimus dose, C0, Cmax, and AUC0-12 were virtually identical in both groups. In a cross-study comparison with data at months 1 and 3 from the pharmacokinetic substudy of the A2307 trial, in which patients received cyclosporine, mean values for everolimus C0, Cmax and AUC0-12 were similar to those in the ASSET trial but the everolimus dose needed to achieve similar exposure was 1.5- to 2-fold higher with concomitant tacrolimus versus cyclosporine. Everolimus exposure is unaffected when tacrolimus exposure is down-titrated within the trough concentration range of 1.5-7 ng/mL. Higher doses of everolimus are needed to achieve a given exposure when combined with tacrolimus versus cyclosporine.