Impact of tacrolimus peak concentration on kidney graft outcomes

Low tacrolimus (Tac) trough concentration-to-dose ratio (C0/D ratio) identifies kidney transplant patients with high level of Tac metabolization and is associated with poorer outcomes. We hypothesized that fast metabolization is associated with higher maximal Tac blood concentration (Cmax) and that Tac Cmax has a detrimental effect by itself. We retrospectively selected consecutive kidney transplant patients who (i) were treated by Tac, (ii) had systematic pharmacokinetic evaluation at 3- and 12-month posttransplant, and (iii) with a minimal follow-up of 5 years. Association between Tac Cmax/C0 with traditional transplant outcomes was analysed. 519 patients with a median follow-up of 8 years were included. Fast metabolizers displayed significantly higher median Cmax (20 vs. 17 ng/mL p < 0.001). Death-censored graft survival (DCGS) was significantly lower for patients with the highest Cmax/C0 values (Log rank, p = 0.05). In multivariate cox analysis, higher Cmax/C0 was independently associated with DCGS (HR = 1.37 [1.01; 1.87], p = 0.043). Our data support the hypothesis that exposure to high Cmax is detrimental and that fast metabolizers exhibit higher Tac Cmax even in situations where Tac C0 is not elevated. Tac formulations prone to mitigate pharmacokinetic peak could thus be particularly beneficial to fast metabolizers and should be evaluated in this indication.