中国患者人群中万古霉素的群体药代动力学研究及药效预测  

Population pharmacokinetics of vancomycin and prediction of pharmacodynamics in the Chinese people

作　　者：何笑荣[1,2] 刘志鹤[2] 季双敏[1] 刘滔滔[3] 李良[1] 周田彦[1] 卢炜[1] 

机构地区：[1]北京大学药学院,北京100191 [2]北京医院药学部,药物临床风险与个体化应用评价北京市重点实验室,北京100730 [3]广西医科大学第一附属医院,广西南宁530021

出　　处：《药学学报》2014年第11期1528-1535,共8页Acta Pharmaceutica Sinica

摘　　要：应用非线性混合效应模型(NONMEM)研究建立中国老年患者万古霉素的群体药代动力学模型。数据为回顾性收集的稀疏数据,采用两中心共260例患者,其中男177例、女83例共计619个血药浓度数据建立模型。采用一室型模型进行数据拟合。两中心数据以引入一个协变量SID(研究中心标识码)的方式考察对模型的影响。最终模型为:1CL=(θbase+θmaxx(1-e(-θxCLcx)))xθAge(Age/72),V=θvXθAge(Age/72)其中的协变量为CLCr和Age,模型CL和V的群体典型值分别2.91 L·h-1,54.76 L。最终模型用Bootstrap法和NPDE法进行模型的内部验证,另外采用34例患者的68个血药浓度数据进行模型的外部验证。Bootstrap法1 000次重复抽样和拟合,通过所得参数的中位数和95%的置信区间判断模型的稳健性。NPDE法和外部数据验证评价模型预测能力。在万古霉素的药效学评价中,用万古霉素群体药动学模型预测的患者清除率计算相应的AUC0-24 h值,以AUC0-24 h与MIC比值大于等于400作为临床有效治疗的指标来判断患者使用万古霉素的合理性。结果显示:部分患者依常规给药时低于理想临床治疗剂量。本研究通过万古霉素的群体药动学模型结合患者的MIC、Age、CLCr及AUC0-24 h/MIC之间的关系来预测万古霉素的合理给药剂量,为患者万古霉素的个体化给药提供参考。Population pharmacokinetics of vancomycin（VAN） in the Chinese patients was described by using nonlinear mixed-effects modeling（NONMEM）. 619 VAN serum concentrations data from 260 patients including 177 males and 83 females were collected separately from two centers. A one-compartment model was used to describe this sparse data. No significant difference was observed between two center datasets by introducing SID covariate. The final model was as 1 CL=（θbase＋θmaxx（1-e^（-θxCLcx）））xθAge（Age/72）,V=θvXθAge（Age/72）The creatinine clearance（CLCr） and Age were identified as the most significant covariate in the final model. Typical values of clearance（CL） and volume of distribution（V） in the final model were 2.91 L·h^-1 and 54.76 L,respectively. Internal model validation by Bootstrap and NPDE were performed to evaluate the robustness and prediction of the final model. The median and 95% confidence intervals for the final model parameterswere based on 1000 Bootstraps. External model evaluation was conducted using an independent dataset that consisted of 34 patients to predict model performance. Pharmacodynamic assessment for VAN by AUC0-24 h to MIC ratios of over 400 was considered to be the best to predict treatment outcomes for patients. AUC0-24 h was calculated by clearance based on the above population model. The results indicate that the conventional dosing regimen probably being suboptimal concentrations in aged patients. The approach via population pharmacokinetic of VAN combined with the relationship of MIC,Age,CLCr and AUC0-24 h/MIC can predict the rational dose for attaining efficacy.

关 键 词：万古霉素 群体药代动力学模型 中国患者 药效学 

分 类 号：R969[医药卫生—药理学]