The effect of CYP3A5 polymorphisms on the pharmacokinetics of tacrolimus in adolescent kidney transplant recipients

Background: CYP3A5 gene polymorphism has been shown to influence tacrolimus (TAC) blood concentration and dose requirement in adult kidney transplant patients. The aim was to analyze retrospectively the modification induced by CYP3A5 gene polymorphism on TAG's pharmacokinetic parameters obtained from 26 adolescents receiving TAC as their main immunosuppressive drug. Material/Methods: The adolescent kidney transplant patients were genotyped for CYP3A5*3 and grouped accordingly. TAC dose, blood levels, and dose-normalized TAC blood concentration and volume of distribution obtained at different post-transplant periods during the first post-transplant year were correlated with the corresponding genotype. Results: During the first three months post-transplant, lieterozygotes (CYP3A5*1/*3) displayed a lower TAC blood concentration than liomozygotes (CYP3A5*3/*3) (at 1 month: 7.8±2.1 vs. 13.4±6 ng/ml, p=0.007) despite a therapeutic monitoring strategy. Between 3-12 months post-transplant, TAC blood concentration was comparable between the two groups, but a two-fold increase in the daily drug dose was necessary for the lieterozygotes (at 6 months: 0.23±0.1 vs. 0.13±0.06 mg/kg, p=0.04). Tlie dose-normalized TAC concentration [(ng/ml)/(mg/kg)] was significantly lower in patients displaying the CYP3A5*1/*3 polymorphism (at 2 weeks: 33±2.16 vs. 71.1±37.8, p=0.01: 6 months: 35.4±12.9 vs. 85.2±58.9, p=0.01). At the same time, the volume of distribution of the drug in the latter group was distinctly increased for the entire post-transplant year (at 6 months: 1.79±0.42 vs. 0.73±6.51/kg, p=0.001). Conclusions: The great influence of CYP3A5 on the pharmacokinetics and pharmacodynamics of TAC in young transplant recipients suggests the need for pre-transplant screening of this polymorphism to improve TAC therapy.