中国健康人群西布曲明的群体药动学模型的建立

Establishment of the population pharmacokinetics model of sibutramine in Chinese healthy volunteers

目的建立中国人群中西布曲明的群体药动学模型。方法 20例男性健康志愿者口服10 mg西布曲明,于服药后0～24 h采集13个采样点采血,采用已验证的HPLC法测定血药浓度。采用非线性混合效应模型(NONMEM)进行群体药动学分析,估算药动学参数。以直观预测检验(Visual predictive check,VPC)和正态预测分布误差(Normalized predictive distribution error,NPDE),Bootstrap法进行模型性能评估。结果以有吸收时滞的一级吸收和消除的二房室模型为西布曲明的基础药动学模型。协变量筛选未见体重、年龄可显著影响模型参数。残差模型选择指数模型。西布曲明群体药动学参数V1,V2,CL,Q,Ka,Tlag的典型值分别为:7.85 L、2.03 L、1.08 L/h、0.289 L/h、1.95/h、0.187 h;个体间变异分别为42.8%、48.2%、38.5%、27.1%、56.8%和17.8%。Bootstrape、拟合优度、VPC和NPDE的评价结果均表明模型稳定,预测结果可靠。结论用非线性混合效应模型法建立的中国人群中西布曲明的群体药动学模型,结果稳定。

Objective To develop the population pharmacokinetics model of sibutramine（SIB） in Chinese healthy volunteers. Methods Twenty male healthy volunteers were enrolled into the study. 13 blood sampling were drawn after administration of 10 mg SIB within 24 h. The plasma samples for SIB concentration were analyzed using validated HPLC/MS method. The population pharmacokinetics was characterized by non-linear mixed effects model （NONMEM）. Visual predictive check （VPC） and normalized predictive distribution error （NPDE） were used to evaluate the predictive ability of the model. The reliability and stability of the population pharmacokinetic model developed was further assessed by a nonparametric bootstrap procedure. Results A two-compartment pharma- cokinetic model with first-order absorption and elimination was used to describe the concentration-time data. The weight and age had no significant impact on the model parameters. The population typical values（ inter-individual variability） of V1, V2,CL, Q, Ka and Tlag were 7.85（42.8%）L,2.03（48.2%）L,1.08（38.5%）L/h,0.289（27.1%）L/h, 1.95（56.8%）h^-1 and 0.187（17.8%） h respectively. Most of parameter estimates from non-parametric bootstrap procedure were comparable and within 10% of the estimates from NONMEM. The stability and the predictive performance were accepted by Bootstrapping, the goodness-of-fit, VPC and NPDE. Conclusion The final population pharmacokinetics model of SIB in Chinese healthy was established by NONMEM. The model was steady and reliable.