Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Anesthesiology, Tianjin Eye Hospital, Tianjin, China.
Eur J Hosp Pharm. 2020 Mar;27(e1):e12-e18. doi: 10.1136/ejhpharm-2018-001764. Epub 2019 Jan 19.
Usage of tacrolimus is complicated by its narrow therapeutic index and wide between- and within-subject pharmacokinetic variability. We aimed to obtain more information regarding the influence of various covariates on the disposition of tacrolimus in the early phase after cardiac transplantation using a population pharmacokinetic method, and provide information for the individualisation of drug dosing in the clinical setting.
Routine therapeutic drug monitoring concentrations (897 observations) were retrospectively collected from 146 hospitalised patients. One compartment model with first-order absorption (absorption rate constant K was fixed as 4.48/hour) was employed to establish the population pharmacokinetic model using a non-linear mixed-effects modelling approach. Various demographic parameters, postoperative day and concomitant medications influencing drug clearance and distribution volume were investigated in this study. Bootstrap and prediction-corrected visual predictive check were employed to validate the final model. With the goal of tacrolimus trough concentrations within the therapeutic window, simulation was performed.
Pharmacokinetic parameter population typical estimates for clearance (CL/F) and apparent distribution volume (V/F) were 14.23 L/hour and 760.80 L, respectively. Postoperative day and co-administration of Wuzhi capsules were identified as important factors affecting CL/F. Total body weight was significantly associated with the V/F. Results of model evaluation indicated a good stable and precise performance of the final model. Based on the simulation results, a simple-touse dosage regimen table to guide clinicians with drug dosing was created.
The final population model could provide information for the individualised dosing of tacrolimus for cardiac transplant recipients.
他克莫司的治疗指数较窄，个体间和个体内药代动力学变异性较大，其应用较为复杂。本研究旨在采用群体药代动力学方法，获得更多关于各种协变量对心脏移植后早期他克莫司处置的影响信息，为临床个体化给药提供依据。
回顾性收集 146 例住院患者的常规治疗药物监测浓度（897 次观察）。采用非线性混合效应模型法，建立一室模型和一级吸收模型（吸收速率常数 K 固定为 4.48/h）。本研究考察了影响药物清除率和分布容积的各种人口统计学参数、术后天数和伴随药物。采用 Bootstrap 和预测校正可视化验证法对最终模型进行验证。模拟目标为使他克莫司谷浓度处于治疗窗内。
清除率（CL/F）和表观分布容积（V/F）的群体典型药代动力学参数估计值分别为 14.23 L/h 和 760.80 L。术后天数和伍智胶囊合用被确定为影响 CL/F 的重要因素。总体重与 V/F 显著相关。模型评价结果表明，最终模型具有良好的稳定性和精确性。基于模拟结果，创建了一个简单易用的剂量方案表，为临床医生提供药物剂量指导。
最终的群体模型可为心脏移植受者个体化他克莫司剂量提供信息。
