#2462 Impact of tacrolimus peak concentration on kidney graft outcomes

Abstract

Abstract Background and Aims Low tacrolimus (Tac) trough concentration-to-dose ratio (C0/D ratio) identifies kidney transplant patients with high level of Tac metabolization and has been shown to be associated with lower graft function and survival. Why fast metabolizers experience poorer outcomes is however unclear. We hypothesized that fast metabolization is associated with higher maximal Tac blood concentration (Cmax) and that Tac Cmax has a detrimental effect by itself. Method We retrospectively selected consecutive kidney transplant patients who (I) were treated by Tac (irrespective of the pharmaceutical formulation), (ii) had systematic abbreviated pharmacokinetic tac evaluation at 3- and 12-months’ post-transplant, and (iii) had a minimal follow-up of 5 years. Fast metabolizers were defined by a C0/D ratio <1.05. Cmax was defined by the higher value of Tac concentration observed at 30, 90 or 180 minutes after Tac morning ingestion and was indexed to C0 in order to exclusively focus on patients with no obvious Tac overexposure. Association between Tac Cmax/C0 with traditional transplant outcomes was analysed by univariate and multivariate cox model and logrank test when appropriate. Results 436 patients transplanted from 2008 to 2016 (64% of male, mean age of 55 ± 13 y) with a median follow-up of 8 years (Q1: 6; Q3: 11) were analysed. Fast metabolizers had lower C0 while receiving higher dose of Tac and displayed significantly higher median Cmax (20 vs 17 μg/l, p < 0.001). Median Cmax/C0 was 3 and 2 in fast and non-fast metabolizers, respectively (p < 0.001). At 15 years’ post-transplant, death-censored graft survival was 13% lower for patients with the highest Cmax/C0 values (p = 0.04). In multivariate cox analysis, higher Cmax/C0 was independently associated with death-censored graft survival (HR = 1.30 (1.03;1.64), p = 0.026). Conclusion Our data support the hypotheses 1—that fast metabolizers exhibit higher Tac Cmax even in situations where Tac C0 are not elevated and 2—that exposure to high Cmax is a potential mechanism underlying their poorer outcome. Tac formulations prone to mitigate pharmacokinetic peak could thus be particularly beneficial to fast metabolizers and should be thoroughly evaluated in this indication.