The Impact of Cytochrome P450 3A5 Genotype on Early Tacrolimus Metabolism and Clinical Outcomes in Lung Transplant Recipients

Abstract

Background Tacrolimus (Tac) is the cornerstone of immunosuppressant therapy after lung transplantation (LTx). It shows great inter-individual variability in pharmacokinetics, which could partly be explained by pharmacogenetic factors. Objective We aim to investigate the effect of cytochrome P450 3A5 (CYP3A5) (rs776746) genotypes on early post-operative Tac metabolism and clinical outcomes in LTx recipients. Methods 90 recipients who underwent LTx from 2017 to 2019 at our institution were enrolled in the study. The effect of CYP3A5 genotype on Tac concentration, dose, dose adjusted concentration (C/D) and interaction with azole antifungals were assessed during week 1–4 after transplantation. Associations between CYP3A5 genotype and the incidence of acute kidney injury (AKI), length of hospital stay and mortality were analyzed. Results CYP3A5*1 carriers had lower C/D than CYP3A5*3/*3 group at all time points (p < 0.05). To reach comparable blood concentrations, CYP3A5*1 carriers required higher doses compared with CYP3A5*3/*3 group (p < 0.05). Use of azole antifungals did not blunt the effect of CYP3A5 genotypes on Tac metabolism. Logistic regression showed Tac concentration at week 1, not CYP3A5 genotype, was associated with the incidence of AKI. No statistically significant difference was found between CYP3A5 genotypes and the length of hospital stay (48 (37–68) vs 46(32–57) days, p = 0.264). Kaplan–Meier analysis showed no statistically significant difference between 30-day or 1-year mortality and CYP3A5 genotype. Conclusion CYP3A5 genotype could affect Tac metabolism early after LTx. However, it has no influence on the incidence of AKI, length of hospital stay and mortality.