他克莫司在151例肝移植受者的常规监测的群体药动学研究

Population Pharmacokinetics of Tacrolimus in Chinese Recipients with Liver Transplantation

目的考察国人肝移植受者口服他克莫司(Tacrolimus,FK506)常规监测的群体药动学特征,为实施个体化用药提供新途径。方法收集151例肝移植受者FK506的血药浓度数据,应用非线性混合效应法(NONMEM)选择药动学模型和统计学模型,并考察性别(GEN)、年龄(AGE)、体重(BW)、术后时间(POD)、剂量(DOSE)、合并用药、肝肾功能、红细胞压积(HCT)等协变量对药动学参数的影响,建立最终回归模型。并根据Bayesian反馈估算获得个体和群体的药动学参数以及预测血药浓度。结果NONMEM法对151例肝移植受者的总数据集用一级吸收二房室开放模型进行拟合,指数模型表征个体间和个体自身变异。将总数据集随机分为建模组和验证组。用建模组数据获得的群体参数在验证组中有较理想的拟合优度。群体药动学参数为:CL为19 L.h-1,V2为170 L,Q为71 L.h-1,V3为324 L,Ka为2.670 h-1,吸收延迟时间(ALAG)为0.230 h。协变量对药动学参数的影响按照OB J下降的幅度依次为DOSE,BUN,HCT对CL;BUN,DOSE,AGE对V2。经Bayesian反馈得到的预测浓度和实测浓度的相关性为r=0.97。模型的误差分析结果表明,平均绝对权重残差(MAWR)为(11±10)%。结论NONMEM法建立回归模型能较好地估算应用FK506的肝移植受者的个体及群体药动学参数,应用回归模型并利用Bayesian反馈可用于临床个体化给药。

OBJECTIVE To evaluate the classic and population pharmaeokinetics of tacrolimus （FK506） oral administration in liver transplant recipients for improving the schedule of individual dosage. METHODS FK506 whole concentration data in 22 recipients and FK506 trough concentration data in 151 recipients were estimated by nonlinear mixed effect model （NONMEM） program. The effects of gender （GEN）, age （AGE）, body weight （BW）, post-operation days （POD）, dosage （DOSE）, concurrent drug , liver function, kidney function, and hematocrit （HCT） on pharmacokinetic parameters were evaluated with structural parameter models. RESULTS There was better result when validation data set was added in the final regression model. The final population parameters were as follows ： CL 19 L. h ^- 1, V2 170 L, Q 71 L. h ^-1, V3 324 L, Ka2. 676 h ^- 1, ALAG 0. 230 h. Mean absolute weighted residual was （ 11 ± 10） %. CONCLUSION The final model of 151 patients could estimate individual and population pharmacokinetic parameters according to individual basic information. Bayesian feedback could be used in individualized administration.