Department of Pharmacology, Toxicology and Pharmacovigilance, Centre Hospitalier Universitaire de Limoges, Limoges, France.
Pharmacology and Transplantation, UMR1248 Inserm Université de Limoges, Limoges, France.
Transpl Int. 2024 Oct 14;37:13495. doi: 10.3389/ti.2024.13495. eCollection 2024.
All the factors potentially influencing tacrolimus dose requirement and combinations thereof have never been thoroughly investigated, precluding accurate prediction of tacrolimus starting dose. This prospective, non-interventional, multicenter study in adult kidney transplant recipients over the first year after transplantation aimed to investigate the factors influencing tacrolimus dose-standardized trough blood concentration (C/D) over the first week post-transplant (D4-D7, primary objective), D8-M3 and M3-M12 (secondary objectives). Statistical analysis employed mixed linear models with repeated measures. Eighteen sites enrolled 440 patients and followed them up for 9.5 ± 4.1 months. Age at baseline ( = 0.0144), end-stage renal disease ( = 0.0092), CYP3A phenotype ( < 0.0001), dyslipidemia at baseline ( = 0.0031), hematocrit ( = 0.0026), total bilirubin ( = 0.0261) and plasma creatinine ( = 0.0484) independently increased with log(C/D) over D4-D7, explaining together 72.3% of the interindividual variability, and representing a robust model to estimate tacrolimus initial dose. Donor age and CYP3A phenotype were also influential over D8-M3 and M3-12, in addition to recipient age. Corticosteroids, diabetes at baseline, and ASAT yielded inconstant results between D8-M3 and M3-M12. We found no ethnicity effect when CYP3A phenotype was accounted for, and no food effect. Intra-individual variability over M3-M12 was moderate, and significantly lower in patients with chronic hepatic disorder ( = 0.0196) or cancer ( = 0.0132).
所有可能影响他克莫司剂量需求的因素及其组合从未被彻底研究过，这使得准确预测他克莫司起始剂量变得不可能。本研究为前瞻性、非干预性、多中心研究，共纳入 440 例成年肾移植受者，旨在研究移植后第 1 年内影响他克莫司剂量标准化谷浓度（C/D）的因素。本研究共分 3 个阶段（D4-D7、D8-M3、M3-M12），D4-D7 为主要终点，D8-M3 和 M3-M12 为次要终点。采用混合线性模型进行重复测量的统计学分析。18 个中心共纳入 440 例患者，平均随访 9.5±4.1 个月。结果显示，年龄（ = 0.0144）、终末期肾病（ = 0.0092）、CYP3A 表型（ < 0.0001）、基线时血脂异常（ = 0.0031）、红细胞压积（ = 0.0026）、总胆红素（ = 0.0261）和血浆肌酐（ = 0.0484）独立于时间因素而增加，解释了 D4-D7 期间 72.3%的个体间差异，是一个强有力的模型，可用于估计他克莫司初始剂量。此外，供体年龄和 CYP3A 表型也影响 D8-M3 和 M3-12，除了受者年龄外。CYP3A 表型也影响 D8-M3 和 M3-12，除了受者年龄外。D8-M3 和 M3-12 期间，皮质类固醇、基线时的糖尿病和丙氨酸氨基转移酶（ASAT）结果不一致。在考虑 CYP3A 表型后，我们发现种族因素无影响，且无食物影响。M3-M12 期间的个体内变异性为中度，且患有慢性肝障碍（ = 0.0196）或癌症（ = 0.0132）的患者显著降低。
