The impact of genetic polymorphisms on time required to attain the target tacrolimus levels and subsequent pharmacodynamic outcomes in pediatric kidney transplant patients

Abstract EN

Recent pharmacogenetic studies involving various transplant recipients in diverse ethnic populations revealed contradictory findings regarding the impact of CYP3A5 and multidrug resistance-1 (MDR1) single nucleotide polymorphisms (SNPs) on the pharmacodynamics of tacrolmius (TAC).

The aim of the current study was to evaluate the impact of these SNPs on the time required to attain target TAC levels and subsequent pharmacodynamic outcomes in pediatric kidney transplant patients.

Thirty-eight patients were genotyped for CYP3A5*1 and *3, and MDR1 C3435T.

Notably, none of the patients expressing CYP3A5 *1*1 or *1*3 achieved the target concentration of 10–20 ng / mL within the first 2 weeks or even the first month after transplant.

However, 34.4 % of CYP3A5 *3*3 achieved and maintained the target goal within the first and second weeks (P < 0.05).

In contrast, C3435T polymorphism had no significant influence on the proportion of patients achieving target TAC levels.

An examination of the impact of genotype combinations on clinical outcomes revealed an increased incidence of acute, chronic rejection and graft loss in patients carrying heterozygous MDR1 C3435T alleles (CT) ; this indicates the possibility of an additive effect of this SNP on its concurrent combination with a *3*3 SNP.

In conclusion, our study revealed trends toward unwanted outcomes in CYP3A5 nonexpressers with an unexplained correlation with MDR1 C3435T polymorphisms.

Recommending routine pharmacogenetic testing of the individual SNPs in renal transplant patients is not yet feasible as the relationship of cost-effectiveness to ultimate impact on graft or patient survival must be justified by further prospective clinical trials.