The Center for Pharmacogenomics and Individualized Therapy, Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA.
Department of Pharmacy, University of North Carolina Hospitals and Clinics, Chapel Hill, NC 27599, USA.
Int J Mol Sci. 2020 Jan 29;21(3):858. doi: 10.3390/ijms21030858.
Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes () and the ATP-binding cassette B1 gene () may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in and and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between or germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and genotype were independently associated with subtherapeutic tacrolimus trough concentrations while or genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.
他克莫司表现出高度的个体间药代动力学（PK）变异性，以及狭窄的治疗指数，因此需要治疗药物监测。细胞色素 P450 同工型 4 和 5 基因（）和 ATP 结合盒 B1 基因（）的种系突变可能导致个体间他克莫司 PK 变异性，这可能影响异基因造血干细胞移植（HSCT）患者的临床结局。在这项研究中，对 252 名接受他克莫司治疗急性移植物抗宿主病（aGVHD）预防的成年 HSCT 患者进行了基因分型，以评估与他克莫司 PK 和药效学（PD）变异性相关的种系遗传变异。在和与 PK 终点（例如，中位稳态他克莫司浓度和达到目标他克莫司浓度的时间）之间检测到种系变异的显著相关性。然而，在或种系变异与 PD 终点（例如，aGVHD 和治疗后发生的肾毒性）之间未观察到显著相关性。年龄和基因型与治疗性他克莫司谷浓度降低独立相关，而基因型、清髓性异基因 HSCT 预处理方案（MAC）和体重增加与治疗性他克莫司谷浓度升高独立相关。有必要进行前瞻性研究，以利用种系遗传和临床数据来开发精确剂量工具，从而优化成年 HSCT 患者的他克莫司剂量和临床结局。
