AUTHOR=Kim Jung Sun , Shim Sunyoung , Yee Jeong , Choi Kyung Hee , Gwak Hye Sun 

TITLE=Effects of CYP3A4*22 polymorphism on trough concentration of tacrolimus in kidney transplantation: a systematic review and meta-analysis

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1201083

DOI=10.3389/fphar.2023.1201083

ISSN=1663-9812

ABSTRACT=<p><bold>Purpose:</bold> Tacrolimus (Tac) is a widely used immunosuppressive agent in kidney transplantation. Cytochrome P450 (CYP), especially <italic>CYP3A4</italic> enzymes are responsible for the metabolism of drugs. However, the correlation between plasma Tac concentration and <italic>CYP3A4*22</italic> gene variants is controversial. This meta-analysis aims to evaluate the association between <italic>CYP3A4*22</italic> polymorphism and the dose-adjusted trough concentration (C<sub>0</sub>/D) of Tac in adult kidney transplant patients.</p><p><bold>Methods:</bold> We conducted a literature review for qualifying studies using the PubMed, Web of Science, and Embase databases until July 2023. For the continuous variables (C<sub>0</sub>/D and daily dose), mean difference (MD) and corresponding 95% confidence intervals (CIs) were calculated to evaluate the association between the <italic>CYP3A4</italic><sup><italic>*</italic></sup><italic>22</italic> and Tac pharmacokinetics. We performed an additional analysis on the relationship of <italic>CYP3A5*3</italic> with Tac PKs and analyzed the effects of <italic>CYP3A4*22</italic> in CYP3A5 non-expressers.</p><p><bold>Results:</bold> Overall, eight eligible studies with 2,683 renal transplant recipients were included in this meta-analysis. The <italic>CYP3A4*22</italic> allele was significantly associated with a higher C<sub>0</sub>/D (MD 0.57 ng/mL/mg (95% CI: 0.28 to 0.86; <italic>p</italic> = 0.0001) and lower mean daily dose requirement (MD -2.02 mg/day, 95% CI: −2.55 to −1.50; <italic>p</italic> &lt; 0.00001). An additional meta-analysis demonstrated that carrying the <italic>CYP3A5*3</italic> polymorphism greatly impacted Tac blood concentration. From the result with CYP3A5 non-expressers, <italic>CYP3A4*22</italic> showed significant effects on the Tac C<sub>0</sub>/D and dose requirement even after adjusting the effect of <italic>CYP3A5*3</italic>.</p><p><bold>Conclusion:</bold> Patients with <italic>CYP3A4*22</italic> allele showed significantly higher plasma C<sub>0</sub>/D of Tac and required lower daily dose to achieve the therapeutic trough level after kidney transplantation. These findings of our meta-analysis may provide further evidence for the effects of genetic polymorphism in <italic>CYP3A4</italic> on the PKs of Tac, which will improve individualized treatment in a clinical setting.</p>