全量采样的他克莫司群体药代动力学分析

摘要

目的:分析中国人他克莫司口服给药的群体药代动力学特征,比较不同用药人群的药代动力学差异.方法:收集健康受试者和肝脏移植患者的他克莫司全量采样药物浓度数据,用非线性混合效应模型(NONMEM)进行群体分析,建立二房室药代动力学模型,个体间变异用指数模型,残差变异用常系数模型,考察吸收速率常数(Ka)、中央室清除率(CL)、中央室分布容积(V2)、室间清除率(Q)、外周室分布容积(V3)等参数在不同组间的差异.通过自举验证、拟合优度、直观预测检验(VPC)来评价最终模型的拟合性能.结果:K3、CL、V2、Q、V3的群体典型值分别是1.09h-1、19.9L·h-1、10.1×(1+CENT×2.34)L、24.8×(1 +CENT× 1.69)L·h-1、353 L,单剂量时ALAG是0.258,个体间变异系数分别是30.2％、71.8％、131％、42.9％、59.7％,不同分析测试方法的残差变异系数分别是8.45％、34.4％,最终模型表明肝脏移植患者的V2和Q比健康受试者的高出2.34和1.69倍.最终模型能较好地预测他克莫司的浓度,浓度观察值(DV)与个体预测值(IPRED)的决定系数R2＝0.82.结论:自举验证、拟合优度评价结果都表明模型稳定,预测性可靠.他克莫司口服给药符合二房室特征,体重对各参数没有显著性影响,肝脏移植患者的V2和Q明显高于健康人群.结果提示不同人群的他克莫司体内药代动力学过程不完全相同.%Objctive: To investigate the difference of tacrolimus population pharmacokinetic between healthy population and patients with liver transplant. Methods: Tacrolimus concentrations were whole sampled from a healthy population and patients with liver transplant, their population pharmacokinetics were evaluated using a nonlinear mixed effect model(NONMEM). A two-compartments pharmacokinetic model was applied while the exponential model was used to describe the inter-individual variability and the constant coefficient model to the residual error, accordingly. Results: The typical values of Ka, CL, V2, Q and V3 were 1.09 h-1, 19.9 L.h-1, 10.1×(l+CENT×2.34) L, 24.8×(l+CENT×l.69) L-h-1 and 353 L respectively. Coefficients of inter-individual variability of Ka, CL, V2, Q and V3 were 68.80%, 73.20%, 119.00%, 62.80% and 83.10%, respectively; and the coefficients of residual error were 8.47% and 39.10%. The final model indicated that the values of V2 and Q in liver transplant patients were higher than those in healthy population at 234% and 169%, respectively. The determination coefficient of observations (DV)-individuals predicted value (IPRED) was 0.82. Conclusion: The final model could predict the tacrolimus concentration fairly well. The stability and the predictive performance were accepted by bootstrapping. The two -compartment model with first-order elimination could describe the pharmacokinetics of tacrolimus fairly well. The population parameter differences between the healthy population and patients with liver transplant indicated that tacrolimus should be applied contrapuntally.