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. Aim We aim to investigate the influence of cytochrome P450 3A5 (CYP3A5) genotypes on early post-LTx Tac metabolism and whether it is affected by concomitant use of azole antifungals. Also, we explored the association between CYP3A5 genotype and clinical outcomes. Method 90 recipients who underwent LTx from 2017 to 2019 were enrolled in the study. The effect of CYP3A5 genotype on Tac metabolism 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. ResultsCYP3A5*1 carriers had lower dose adjusted concentration (C/D) than CYP3A5*3/*3 group at all time points (p < 0.05). The dose ratio of CYP3A5*1 carriers to CYP3A5*3/*3 was between 1.3 and 2.4 when comparable concentrations were reached. Use of azole antifungals did not blunt the effect of CYP3A5 genotypes on Tac metabolism. Logistic regression showed Tac concentration ≥ 7.5 ng/mL at week 1 was associated with higher incidence of AKI. No statistically significant difference was found between CYP3A5 genotypes and the length of hospital stay. 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 had no influence on the incidence of AKI, length of hospital stay and mortality.
Highlights
Tacrolimus (Tac) is the cornerstone of immunosuppressant therapy after lung transplantation (LTx) [1]
No statistically significant difference was found between cytochrome P450 3A5 (CYP3A5) genotypes and the length of hospital stay (48 (37–68) vs 46(32–57) days, p = 0.264)
We drew three major conclusions from the data: (1) patients bearing CYP3A5*1 allele showed significantly lower Tac C/D and higher dose requirement compared with *3/*3 genotype in the early post-operative period; (2) the use of azole antifungals did not change the influence of CYP3A5 genotype on Tac metabolism; (3) CYP3A5 genotype has no effect on the incidence of acute kidney injury (AKI), length of hospital stay or mortality
Summary
Tacrolimus (Tac) is the cornerstone of immunosuppressant therapy after lung transplantation (LTx) [1]. It is essential to reach target range of Tac concentration as soon as possible in the early post-transplant period, since erratic concentration may increase the incidence of rejection [2], nephrotoxicity [3] and even affects mortality [4]. This attempt is usually hampered by its highly variable pharmacokinetics [5]. Tacrolimus (Tac) is the cornerstone of immunosuppressant therapy after lung transplantation (LTx) It shows great interindividual variability in pharmacokinetics, which could partly be explained by pharmacogenetic factors
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