Impact of CYP3A5 1* and 3* single nucleotide variants on tacrolimus pharmacokinetics and graft rejection risk in pediatric kidney transplant patients.

Tacrolimus, a calcineurin inhibitor, is widely used to prevent allograft rejection in kidney transplant recipients. Its metabolism is predominantly mediated by the cytochrome P450 3A5 (CYP3A5) enzyme, and single nucleotide variants (SNVs) within intron 3 of the gene are strongly associated with interindividual variability in enzyme expression and activity. These SNVs can generate a cryptic splice site, resulting in either preserved enzymatic function classified as expressers ( *1/*1 and *1/*3) or loss of function, classified as non-expressers ( *3/*3). Differential expression of contributes to variability in tacrolimus pharmacokinetics and clinical outcomes, including graft rejection and therapeutic efficacy. In this study, we evaluated three pharmacokinetic parameters: trough concentration (TAC-C), weight-adjusted daily dose (TAC-D, mg/kg), and dose-normalized trough concentration (TAC-C/D). One-way ANOVA was used to assess differences in these parameters between expressers and non-expressers. Additionally, Poisson regression was performed to examine associations between clinical/genetic variables and the incidence rate of acute rejection events. Genotyping was conducted in 45 pediatric kidney transplant recipients. The *3/*3 genotype was most prevalent (66.7%), followed by *1/*3 (26.7%) and *1/*1 (6.7%). During the 6-month post-transplant period, expressers required significantly higher tacrolimus doses to achieve target trough levels. Increased drug exposure was associated with a higher incidence of rejection events, whereas expression correlated with a reduced rate of rejection. These findings underscore the clinical utility of genotyping for optimizing tacrolimus dosing strategies. Carriers of functional alleles (*1/*3 or *1/*1) benefit from individualized dose adjustments to achieve therapeutic concentrations and reduce the risk of graft rejection.