CYP3A5 Genotype-Dependent Drug-Drug Interaction Between Tacrolimus and Voriconazole in Chinese Kidney Transplant Patients.

Abstract

The effect of drug-drug interaction (DDI) between tacrolimus and voriconazole on the pharmacokinetics of tacrolimus in different CYP3A5 genotypes has not been reported in previous studies. The objective of this study was to investigate whether CYP3A5 genotype could influence tacrolimus-voriconazole DDI in Chinese kidney transplant patients. All kidney transplant patients were divided into combination and non-combination groups based on whether tacrolimus was combined with or without voriconazole. Each group was subdivided into CYP3A5 expresser (CYP3A5*1/*1 or CYP3A5*1/*3) and CYP3A5 nonexpresser (CYP3A5*3/*3). A retrospective analysis compared tacrolimus dose (D)-corrected trough concentrations (C0) (C0/D) between combination and non-combination groups, respectively. Tacrolimus C0/D was also compared between CYP3A5 expresser and nonexpresser in both groups. The C0/D values of tacrolimus were significantly different between CYP3A5 expresser and nonexpresser in combination group (378.20 [219.38, 633.48] ng/mL/[mg/kg/d] vs 720.00 [595.35, 1681.50] ng/mL/[mg/kg/d], P = 0.0010). Either in CYP3A5 expresser or nonexpresser, we found a statistically significant difference in tacrolimus C0/D between combination and non-combination group (P < 0.0001). The increase in CYP3A5 nonexpresser was 1.38 times higher than that in CYP3A5 expresser (320.93% vs 232.19%). The median C0/D values were 90.38% higher in kidney transplant recipients with CYP3A5*3/*3 genotype than in those with CYP3A5*1/*1 or CYP3A5*1/*3 genotype when treated with both tacrolimus and voriconazole. A CYP3A5 genotype-dependent DDI was found between tacrolimus and voriconazole. Therefore, personalized therapy accounting for CYP3A5 genotype detection and therapeutic drug monitoring is necessary for kidney transplant patients when treating with tacrolimus and voriconazole.