P2082Investigation of tacrolimus metabolism through CYP3A enzymes after cardiac transplantation

Abstract

Introduction: Immunosuppressive regime, especially tacrolimus (TAC) dosing after cardiac transplantation (HTX) should be carefully tailored to avoid rejection, side effects and infection. TAC is metabolized by the CYP3A enzyme family. Polymorphism of these genes may lead to greatly differing TAC doses. Purpose: Our aim was to investigate the correlation between CYP3A5 genotype and CYP3A4 mRNS expression and of the TAC dose required to achieve stable trough levels. Methods: We included 54 consecutive transplanted patients, all treated with the same immunosuppressive regime (pharmacogenetic study performed: CYP1, n=35; not performed: CYP0, n=19). Results: According to our results, 17% of the investigated patients showed CYP3A5∗1/∗3 heterozygous genotype which results in active CYP3A5 enzyme. The CYP3A5∗3/∗3 homozygous patients metabolize TAC solely through the CYP3A4 enzyme. In the latter group, 55% had low and 45% had normal CYP3A4 mRNS expression. The CYP3A5 heterozygous patients had a significantly higher TAC dose requirement to achieve therapeutic TAC trough level as compared to the CYP3A5∗3/∗3 homozygous patients (0.17±0.06 vs. 0.11±0.05 mg/kg, p=0.03), independently of their CYP3A4 mRNS expression. While the clinical application of these pharmacogenetic results were not obligatory for the treating physician, the CYP1 group had a significantly better renal function after HTX (worst post‐HTX GFR: 52±24 vs. 37±24 ml/min/1.73m2, p=0.04) and significantly lower need for dialysis (11% vs. 37%, p<0.05). Conclusions: We may conclude, that the analysis of TAC metabolism, especially identifying CYP3A5∗1/∗3 heterozygous HTX patients may be an effective tool in optimizing TAC dosing. Application of the pharmacogenetic results may improve post‐HTX renal function and may help in avoiding dialysis treatment.