Influence of CYP3A4*22 and CYP3A5*3 combined genotypes on tacrolimus dose requirements in Egyptian renal transplant patients.

BACKGROUND

Tacrolimus is a widely prescribed immunosuppressant agent for kidney transplantation. However, optimal dosing is challenging due to its narrow therapeutic index, potentially serious adverse effects, and wide inter-individual variability in pharmacokinetics. Cytochrome P450 3A (CPY3A) enzymes metabolize tacrolimus, so allelic variants such as CYP3A422 and CYP3A53 may contribute to individual differences in pharmacokinetics and therapeutic efficacy of tacrolimus. This study assessed the frequency and influences of CYP3A422 and CYP3A53 genotypes, alone and combined, on tacrolimus pharmacokinetics and dose requirements in Egyptian kidney transplant patients.

METHODS

This is a prospective multicenter observational cohort study. Patients were genotyped for the CYP3A422 (rs35599367), and CYP3A53 (rs776746). Tacrolimus dose (mg), through blood level (ng/ml), and dose-adjusted trough concentration (C0/D) (ng/ml per mg/kg) were recorded during the first and third months post-transplantation and compared among genotype groups.

RESULTS

The CYP3A422 allele was rare (3.2% of subjects) while the CYP3A53 allele was widespread (90.38%) in this cohort. At the third month post-transplantation, median C0/D was significantly higher among CYP3A422 carriers than CYP3A41/1 (146.25 [100-380] versus 85.57 [27-370] ng/ml per mg/kg, p = 0.028). Patients harbouring the one copy of the CYP3A422 allele and the CYP3A5*3/3 genotype (n = 5) were classified as poor tacrolimus metabolizers, the CYP3A53/3 plus CYP3A41/1 genotype as intermediate metabolizers (n = 60), and the CYP3A41/1 plus CYP3A51/*1 genotype as normal metabolizers (n = 13). During the first month post-transplantation, C0/D was significantly greater in poor metabolizers (113.07 ng/ml per mg/kg) than intermediate and normal metabolizers (90.380 and 49.09 ng/ml per mg/kg) (p < 0.0005). This rank order was also observed during the third month. Acute rejection rate and renal function at discharge did not differ among genotypes.

CONCLUSION

Pharmacogenetics testing for CYP3A422 and CYP3A53 before renal transplantation may help in the adjustment of tacrolimus starting dose and identify patients at risk of tacrolimus overexposure or underexposure.