Effect of CYP3A Genetic Variants on Different Measures of Tacrolimus Variability in Heart Transplant Recipients

Abstract

CYP3A genetic variants are associated with tacrolimus (TAC) dose requirements and levels. However, the contribution of CYP3A genetics to variability in TAC levels is unclear. We sought to determine the relationship between CYP3A genetic variants and three measures of TAC variability, i.e., coefficient of variation (CV) of dose-adjusted trough levels (C0/D), time in therapeutic range (TTR), and TTR via the Rosendaal method (Rosendaal TTR), in adult heart transplant (HTx) recipients. This was a retrospective study of 69 HTx recipients during the first-year post-HTx. Patients were grouped as CYP3A5 expressors (CYP3A5*1/*1 or *1/*3) or non-expressors (CYP3A5*3/*3) and CYP3A4 non-carriers (CYP3A4*1/*1) or carriers (CYP3A4*1/*22 or *22/*22). Combined CYP3A phenotypes included extensive (EM, CYP3A5*1 carrier + CYP3A4*1/*1) vs intermediate (IM, CYP3A5*3/*3 + CYP3A4*1/*1) vs poor (PM, CYP3A5*3/*3 + CYP3A4*22 carrier) metabolizers. TAC data were extracted from medical records. The primary outcome was TTR. Secondary outcomes were CV of C0/D and Rosendaal TTR. Data were analyzed using generalized linear models. The study consisted of 80% men and 78% Caucasians (mean age at HTx=50 ± 13 years). Mean TTR, CV, and Rosendaal TTR were 30.9 ± 13.6%, 42.5 ± 21.0%, and 37.4 ± 19.8%, respectively. TAC-CYP3A variability data are shown in the table. TAC TTR was significantly lower in CYP3A5 expressors vs non-expressors, 24.0% (95% CI=18.0 to 30.1) vs 33.3% (95% CI=29.7 to 37.0), p=0.010. Similar findings were observed for combined CYP3A phenotype, with differences largely driven by CYP3A5 genotype. Neither CYP3A5 nor CYP3A4 genetics were significantly associated with CV or Rosendaal TTR. Of the three measures of variability evaluated in our cohort, CYP3A5 genetics was only associated with TAC TTR. These findings suggest that different measures of TAC variability may elicit different findings in pharmacogenomic association studies of HTx recipients.