The effect of CYP3A5 gene polymorphism on the pharmacokinetics of tacrolimus in heart transplant recipients

Objective: to assess the association between CYP3A5 isoenzyme genotypes and tacrolimus (Tac) dose and whole-blood levels in heart transplant (HT) recipients in the early and long-term post-transplant periods. Materials and methods. The study included 189 HT recipients receiving Tac as part of their maintenance immunosuppressive therapy. CYP3A5 polymorphisms (*1/*1, *1/*3, *3/*3) were determined via real-time polymerase chain reaction. Tac dose and whole-blood concentrations were evaluated at 1 month, 1 year, and at long-term follow-up (>1 year; mean 7.0 ± 3.1 years) after HT. In addition, general and biochemical blood test results were analyzed. Results. The CYP3A5 *3/*3 genotype was predominant among HT recipients (89%), while the *1/*3 genotype was identified in 10% and the *1/*1 genotype in 1% of patients. Carriers of the *1 allele (*1/*3 and *1/*1) required substantially higher Tac doses – approximately twofold or greater – compared with *3/*3 carriers at all follow-up time points: at 1 month post-transplant, median doses were 8.0 [6.0–10.25] mg and 11.0 [9.5–12.5] mg versus 4.0 [3.0–6.0] mg (p < 0.001); at 1 year, 8.0 [6.0–9.0] mg and 10.0 [9.0–11.0] mg versus 3.0 [2.0–5.0] mg (p < 0.001); and at long-term follow-up, 7.0 [6.0–8.0] mg and 9.0 [7.5–10.5] mg versus 3.0 [2.0–5.0] mg (p < 0.001). Tac whole-blood levels did not differ significantly between groups of heart recipients at any time point during follow-up. However, the concentration-to-dose ratio (C0/D) was significantly higher in *3/*3 carriers across all follow-up periods (p = 0.000). At long-term follow-up, patients with the *3/*3 genotype exhibited significantly higher median serum creatinine levels compared with carriers of the *1 allele (107.6 [87.3–142.1] μmol/L vs 90.2 [75.0–99.7] μmol/L; p = 0.001). Correlation analysis revealed significant associations between Tac levels and white blood cell count (r = 0.148; p = 0.027), total bilirubin levels (r = 0.217; p < 0.001), and cholesterol levels (r = –0.274; p < 0.001). Conclusion. The non-expressing CYP3A5 *3/*3 genotype is predominant among HT recipients (89%). Carriers of the functional CYP3A5 *1 allele (*1/*3 and *1/*1) require twofold or higher Tac doses to achieve target whole-blood levels compared with *3/*3 carriers. These findings confirm that CYP3A5 polymorphism is a major determinant of interindividual variability in Tac pharmacokinetics in HT recipients. Pre-treatment pharmacogenetic testing for CYP3A5 may facilitate individualized dosing strategies, enabling more rapid attainment of therapeutic drug levels.

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