Impact of fast tacrolimus metabolizer status on outcome after heart transplantation
Authors: Oehler D , Boettger C , Sigetti D , Voss F , Hettlich V H , Herzum P , Jenkins F S , Aubin H , Scheiber D , Horn P , Boenner F , Polzin A , Kelm M , Lichtenberg A , Boeken U 
Published: November 2023

Abstract

Objective
Optimal immunosuppression is an essential component of the best possible long-term survival after heart transplantation (HTX). Optimally patient-tailored immunosuppression is standard in Tx follow-up, balancing harmful side effects and preventing rejection episodes. Hereby, stable blood levels, as well as a stable and calculable absorption rate, is essential. Tacrolimus additionally has a narrow therapeutic range and is particularly difficult to dose stably. It has been shown that interindividual differences in absorption exist among various immunosuppressants, making adequate minimum levels and the avoidance of rejection events more difficult. For other solid organ transplantation procedures there are already studies on the proportion of patients (so-called "fast metabolizers") who experience different kinetics due to very rapid resorption. We here therefore aim to investigate the potential impact of the tacrolimus metabolizer status on outcome in a HTx cohort.

Methods
We defined fast metabolizers by a low concentration to dose ratio (C/D ratio) of &lt;1.05. The C/D ratio was determined according to the following formula: C/D ratio (ng/ml x 1/mg) = Tacrolimus through level (ng/ml) / daily Tacrolimus dose (mg).
We included as a first step here 57 patients undergoing HTx in our center between 09/2010 and 10/2016 and calculated the C/D ratio retrospectivley from routine follow-ups. In both groups baseline characteristics, perioperative parameters and survival after 1 and 5 years after Tx were collected.

Results
We identified 24 patients (42%) as fast metabolizers and 33 patients as standard metabolizers (58%). The metabolizer status did not significantly correlate with reduced survival of the recipient up to 5 years in Kaplan-Meier-Analysis (Figure 1,A, Log Rank p=0.68). Additionally, regression analysis could not detect an association of 1-year-survival and C/D ratio or the fast metabolizer status definition (HR 1.1, 95% CI 0.17-7.2, p=0.92). Moreover, using ROC-analysis, no clear other cut-off for C/D ratio other than the used published definition (&lt;1.05) could be derived (Figure 1,B, AUC 5-year survival 0.53, p = 0.72). Additionally, these parameters did not change significantly also when focusing on speficic substances with different pharmacodynamics such as Prograf (two doses per day) or Advagraf (delayed release, one dose per day). We could also not detect associations between C/D ratio or metabolizer status and unfavorable outcomes such as cellular or clinical relevant rejection episodes.

Conclusion
In this retrospective analysis, neither the metabolizer status or the raw tacrolimus concentration to dose ratio was associated with altered survival or outcome after heart transplantation. As we present here a yet small number of investigated patients (pilot study) with a potential era bias by currently not including advances in medication optimization over the last years, future studies are needed to elucidate this phenomen further.