Abstract

BACKGROUND: Pharmacokinetic data regarding a drug-drug interaction between everolimus and tacrolimus are sparse.

MATERIAL AND METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.

Keywords: Kidney Transplantation, Pharmacokinetics, Tacrolimus