Chen B, Shi H-Q, Liu X-X, Zhang W-X, Lu J-Q, Xu B-M, Chen H
Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Organ Transplantation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Clin Pharm Ther. 2017 Dec;42(6):679-688. doi: 10.1111/jcpt.12599. Epub 2017 Aug 17.
Tacrolimus (TAC) is widely used as part of immunosuppressive regimens. There is great interindividual variation on the disposition of TAC. The aim of this study was to develop a population pharmacokinetic (PPK) model for Chinese liver transplant patients and evaluate genetic polymorphism and other possible factors on the PK parameters. The exposure of TAC is to be estimated through Bayesian modelling.
A total of 47 sets of rich-time PK and 1234 conventional therapeutic drug monitoring (TDM) data were collected from 125 Chinese liver transplant patients. The pathophysiological data of these patients were recorded. CYP3A5*3 and ABCB1 genotypes were determined for each patient. The PPK model for TAC was established by nonlinear mixed-effects modelling (nonmem). The impact of pathophysiology and genotype on PPK parameters was evaluated. Bayesian estimators for the area under concentration-time curve (AUC) of TAC were validated.
A two-compartment model with lag time was found to be the most suitable model for the pooled full PK and TDM data for Chinese liver transplant patients. The CL/F, V /F, Q/F, V /F, K and lag time were 17.4±0.81 L/h, 165±44.1 L, 54.9±25.8L/h, 594±87.5 L, 0.51±0.095 L/h and 1.57±0.34 h. Post-operative day (POD), creatinine clearance (CLcr) and ABCB1 C3435T genotypes were found to have significant influences on CL/F (P<.01). ABCB1 C3435T genotypes showed a significant correlation with V /F (P<.01). C -C and C -C -C were shown to be suitable for the estimation of AUC in Chinese liver transplant patients.
A PPK model for TAC was established successfully in Chinese liver transplant patients. POD, CLcr and ABCB1 C3435T genotypes were shown to have significant effects on CL/F. The AUC of TAC in Chinese liver transplant patients could be estimated through Bayesian modelling, based on which individualized immunosuppressive regimens can be designed.
他克莫司（TAC）作为免疫抑制方案的一部分被广泛应用。TAC的处置存在很大的个体差异。本研究的目的是为中国肝移植患者建立群体药代动力学（PPK）模型，并评估基因多态性及其他可能因素对药代动力学参数的影响。将通过贝叶斯建模估计TAC的暴露量。
从125例中国肝移植患者中收集了47组丰富时间药代动力学数据和1234份常规治疗药物监测（TDM）数据。记录这些患者的病理生理数据。测定每位患者的CYP3A5*3和ABCB1基因型。通过非线性混合效应建模（nonmem）建立TAC的PPK模型。评估病理生理学和基因型对PPK参数的影响。对TAC浓度-时间曲线下面积（AUC）的贝叶斯估计值进行验证。
对于中国肝移植患者的汇总全药代动力学和TDM数据，发现具有滞后时间的二室模型是最合适的模型。清除率（CL/F）、分布容积（V/F）、中央室清除率（Q/F）、周边室分布容积（V/F）、消除速率常数（K）和滞后时间分别为17.4±0.81L/h、165±44.1L、54.9±25.8L/h、594±87.5L、0.51±0.095L/h和1.57±0.34h。术后天数（POD）、肌酐清除率（CLcr）和ABCB1 C3435T基因型对CL/F有显著影响（P<0.01）。ABCB1 C3435T基因型与V/F有显著相关性（P<0.01）。C-C和C-C-C被证明适用于估计中国肝移植患者的AUC。
在中国肝移植患者中成功建立了TAC的PPK模型。POD、CLcr和ABCB1 C3435T基因型对CL/F有显著影响。基于贝叶斯建模可以估计中国肝移植患者TAC的AUC，并据此设计个体化免疫抑制方案。
