Effect of CYP3A4*22 and CYP3A5 Combined Genotypes on Tacrolimus Disposition in Heart Transplantation

The CYP3A4*22 and CYP3A5*3 polymorphisms have been associated with decreased tacrolimus (TAC) metabolism and decreased TAC dose requirements in numerous transplant (Tx) populations. The objective of this study was to determine the combined impact of CYP3A4*22 and CYP3A5*3 genotypes on TAC disposition in heart transplant (HTx) recipients. HTx patients who were greater than 1 year post-Tx and receiving TAC were included in this cross-sectional study. TAC trough levels and doses were abstracted from medical records. Patients were genotyped for the CYP3A4*22 and CYP3A5*3 polymorphisms. Combined phenotypes were assigned as follows: Extensive metabolizers (EM, CYP3A4*1/*1+CYP3A5*1 carriers); Intermediate metabolizers (IM, CYP3A4*1/*1+CYP3A5*3/*3, or CYP3A4*22 carriers+CYP3A5*1 carriers), and Poor metabolizers (PM, CYP3A4*22 carriers+CYP3A5*3/*3). The primary endpoint was the dose-adjusted TAC level (L/D, ng/ml per mg/day). Data were analyzed using generalized linear model analysis, with diltiazem use (yes/no) and the number of days post-Tx on the day of the TAC level included as covariates in the adjusted analysis. The study included n=74 HTx patients receiving TAC (81% men; 85% white; age=54 ± 16 years; time post-Tx=3278 ± 2270 days; mean TAC L/D=3.1 ± 1.6 ng/ml per mg/day). In singular analysis, the adjusted mean TAC L/D was 21% higher in patients with the CYP3A4*1/*22 genotype (n= 11) than in CYP3A4*1 homozygotes (n=63), although this did not reach statistical significance (p=0.20). Adjusted mean TAC L/D was 67% higher in CYP3A5*3 homozygotes (n=59) versus CYP3A5*1 carriers (n=15; p=0.002). When combined CYP3A4*22 and CYP3A5 genotypes were evaluated, adjusted mean TAC L/D was 77% higher in PMs (n=11) versus EMs (n=15), and 63% higher in IMs (n=48) versus EMs (n=15); p=0.008 overall for metabolizer status. CYP3A4*22 and CYP3A5 combined genotypes influenced TAC L/D in HTx recipients. This finding appears to be mostly driven by the effect of the CYP3A5*3 polymorphism on TAC disposition. Additional studies are needed to determine the impact of CYP3A4*22 and CYP3A5 combined genotypes on TAC dose predictions and outcomes following HTx. This work was funded, in part, by a grant from the American Heart Association (12GRNT12040211).