论文部分内容阅读
目的考察肝移植受者口服环孢素的群体药动学特征,为实施个体化用药提供新途径。方法回顾性收集120例肝移植病人全血稳态谷浓度样本1 947个,利用NONMEM软件考察一天给药剂量,分析其群体药动学模型,估算参数、个体间变异(interindividual variability,IIV)、时间效应变异(interoccasion variability,IOV)和个体内变异,定量考察人口统计学资料、生理状态、肝肾功能和合并用药等因素对药物药动学参数的影响,建立最终回归模型,应用POSTHOC子模块反馈获得个体和群体的药动学参数及预测给药剂量。模型验证用近似外部验证和bootstrap内部验证法。结果环孢素稳态浓度能用米曼氏模型较好的拟合,最终群体药动学参数Vm为303 mg.d-1,Km为14.90μg.L-1。Vm和Km的IIV分别为12.60%和89.78%,IOV分别为12.30%和36.88%,残差变异为4.00%。Vm结构模型参数有用药天数(DT)、红细胞压积(HCT)、总蛋白(TP)、尿素(BUN)、甘油三酯(TG)、吗替麦考酚酸酯剂量(MMF)。Km结构模型参数有胆红质(DBIL)和泼尼松剂量(PR)。结论NON-MEM法考察临床常规监测数据应当考虑IOV,分析得到的群体药动学模型可为临床患者提供用药依据。
Objective To investigate the population pharmacokinetic characteristics of oral cyclosporine in liver transplant recipients and to provide a new way for individualized drug use. Methods A total of 1 947 steady-state trough concentrations of whole blood in 120 patients with liver transplantation were retrospectively collected. The dose of one day was investigated by NONMEM software. The population pharmacokinetic model, estimated parameters, interindividual variability (IIV) Time variability (IOV) and in-vivo variability, and quantitatively investigated the effects of demographic data, physiological status, liver and kidney function and drug combination on the pharmacokinetic parameters. The final regression model was established. POSTHOC submodule Feedback to obtain individual and group pharmacokinetic parameters and predict the dose. Model validation uses approximate external validation and bootstrap internal validation. Results The steady-state concentration of cyclosporine could be fitted well by the Miemann’s model. The final population pharmacokinetic parameters Vm was 303 mg.d-1 and Km was 14.90μg.L-1. The IIV of Vm and Km were 12.60% and 89.78% respectively, the IOV was 12.30% and 36.88% respectively, and the residual variation was 4.00%. Vm structural model parameters useful drug days (DT), hematocrit (HCT), total protein (TP), urea (BUN), triglyceride (TG), mycophenolate mofetil dose (MMF). Km structural model parameters were bilirubin (DBIL) and prednisone dose (PR). Conclusions The IOV should be considered when examining clinical routine monitoring data by NON-MEM method. The analyzed population pharmacokinetic model can provide evidence for clinical use.