Kim Jung Sun, Shim Sunyoung, Yee Jeong, Choi Kyung Hee, Gwak Hye Sun
College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea.
College of Pharmacy, Gachon University, Incheon, Republic of Korea.
Front Pharmacol. 2023 Jul 26;14:1201083. doi: 10.3389/fphar.2023.1201083. eCollection 2023.
Tacrolimus (Tac) is a widely used immunosuppressive agent in kidney transplantation. Cytochrome P450 (CYP), especially enzymes are responsible for the metabolism of drugs. However, the correlation between plasma Tac concentration and gene variants is controversial. This meta-analysis aims to evaluate the association between polymorphism and the dose-adjusted trough concentration (C/D) of Tac in adult kidney transplant patients. 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/D and daily dose), mean difference (MD) and corresponding 95% confidence intervals (CIs) were calculated to evaluate the association between the and Tac pharmacokinetics. We performed an additional analysis on the relationship of with Tac PKs and analyzed the effects of in CYP3A5 non-expressers. Overall, eight eligible studies with 2,683 renal transplant recipients were included in this meta-analysis. The allele was significantly associated with a higher C/D (MD 0.57 ng/mL/mg (95% CI: 0.28 to 0.86; = 0.0001) and lower mean daily dose requirement (MD -2.02 mg/day, 95% CI: -2.55 to -1.50; < 0.00001). An additional meta-analysis demonstrated that carrying the polymorphism greatly impacted Tac blood concentration. From the result with CYP3A5 non-expressers, showed significant effects on the Tac C/D and dose requirement even after adjusting the effect of . Patients with allele showed significantly higher plasma C/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 on the PKs of Tac, which will improve individualized treatment in a clinical setting.
他克莫司（Tac）是肾移植中广泛使用的免疫抑制剂。细胞色素P450（CYP），尤其是酶，负责药物的代谢。然而，血浆他克莫司浓度与基因变异之间的相关性存在争议。本荟萃分析旨在评估多态性与成年肾移植患者他克莫司剂量调整后的谷浓度（C/D）之间的关联。我们使用PubMed、Web of Science和Embase数据库对截至2023年7月的合格研究进行了文献综述。对于连续变量（C/D和每日剂量），计算平均差（MD）和相应的95%置信区间（CIs）以评估与他克莫司药代动力学之间的关联。我们对与他克莫司药代动力学的关系进行了额外分析，并分析了在CYP3A5非表达者中的作用。总体而言，本荟萃分析纳入了八项符合条件的研究，共2683名肾移植受者。等位基因与较高的C/D显著相关（MD 0.57 ng/mL/mg（95%CI：0.28至0.86；=0.0001））和较低的平均每日剂量需求（MD -2.02 mg/天，95%CI：-2.55至-1.50；<0.00001）。另一项荟萃分析表明，携带多态性对他克莫司血药浓度有很大影响。从CYP3A5非表达者的结果来看，即使在调整了的影响后，对他克莫司C/D和剂量需求仍有显著影响。携带等位基因的患者肾移植后他克莫司的血浆C/D显著更高，且达到治疗谷浓度所需的每日剂量更低。我们荟萃分析的这些发现可能为基因多态性对他克莫司药代动力学的影响提供进一步证据，这将改善临床环境中的个体化治疗。
