The impact of CYP3A4 and CYP3A5 genetic variations on tacrolimus treatment of living‐donor Egyptian kidney transplanted patients

Abstract

AbstractBackgroundTacrolimus (TAC) is the mainstay of immunosuppressive regimen for kidney transplantations. Its clinical use is complex due to high inter‐individual variations which can be partially attributed to genetic variations at the metabolizing enzymes CYP3A4 and CYP3A5. Two single nucleotide polymorphisms (SNPs), CYP3A4*22 and CYP3A5*3, have been reported as important causes of differences in pharmacokinetics that can affect efficacy and/or toxicity of TAC.ObjectiveInvestigating the effect of CYP3A4*22 and CYP3A5*3 SNPs individually and in combination on the TAC concentration in Egyptian renal recipients.MethodsOverall, 72 Egyptian kidney transplant recipients were genotyped for CYP3A4*22 G>A and CYP3A5*3 T>C. According to the functional defect associated with CYP3A variants, patients were clustered into: poor (PM) and non‐poor metabolizers (Non‐PM). The impact on dose adjusted through TAC concentrations (C0) and daily doses at different time points after transplantation was evaluated.ResultsCyp3A4*1/*22 and PM groups require significantly lower dose of TAC (mg/kg) at different time points with significantly higher concentration/dose (C0/D) ratio at day 10 in comparison to Cyp3A4*1/*1 and Non‐PM groups respectively. However, CyP3A5*3 heterozygous individuals did not show any significant difference in comparison to CyP3A5*1/*3 individuals. By comparing between PM and Non‐PM, the PM group had a significantly lower rate of recipients not reaching target C0 at day 14.ConclusionThis is the first study on Egyptian population to investigate the impact of CYP3A4*22 and CYP3A5*3 SNPs individually and in combination on the TAC concentration. This study and future multicenter studies can contribute to the individualization of TAC dosing in Egyptian patients.