中国成年感染患者万古霉素群体药动学研究  

Population Pharmacokinetics of Vancomycin in Chinese Adult Infection Patients

作　　者：林忠[1] 陈敏方 崔可[1] 张超[1] 余国亮[1] 杨伟英[1] 孙渊[1] 陈赛贞[1] 黄如意[3] 谢群丽 朱燕舞[1] LIN Zhong CHEN Minfang CUI Ke ZHANG Chao YU Guoliang YANG Weiying SUN Yuan CHEN Saizhen HUANG Ruyi XIE Qunli ZHU Yanwul(Clinical Pharmacy Experimental Center, Taizhou Hospital of Zhejiang Province, Taizhou 317000, China Wenlin Traditional Chinese Medicine, Taizhou 318000, China Wenzhou Medical College, Wenzhou 325035, China)

机构地区：[1]浙江省台州医院药剂科临床药学实验中心,浙江台州317000 [2]浙江省温岭中医院,浙江台州318000 [3]温州医科大学,浙江温州325035

出　　处：《中国现代应用药学》2017年第1期101-106,共6页Chinese Journal of Modern Applied Pharmacy

基　　金：台州市科技基金(14SF03);恩泽科研基金(12ED31);台州市医学会科学研究基金(TZSYXH15-12);浙江省卫生厅科研基金(2015KYB436)

摘　　要：目的利用来自恩泽医疗中心3家医院的成年万古霉素治疗患者的治疗药物监测数据研究其群体药动学(population pharmacokinetics,PPK)模型,并利用所建药动学参数模型和该类群体患者治疗过程中的单点谷浓度经贝叶斯反馈参数估算法计算个体化药动学参数,建立个体化给药方案。方法收集128例患者,共监测235个血清浓度,采用Kinetica软件的PPK模块中的一室静脉给药模型通过期望最大法(EM)和贝叶斯反馈拟合数据得到基础模型。利用逐步正向回归法研究消除速率常数(Kel和Vd)与患者个体协变量肌酐(Scr)、年龄(Age)、体质量(Wt)、性别(Sex)以及合并用药之间的关系,并拟合最终模型。利用内部自举法和外部验证法对模型进行评价。结果本研究中最终模型公式为Kel=θ_1×(Scr)^(θ_2)×(Sex)^(θ_3),V=θ_4×(Scr)^(θ_5)×(Age)^(θ_6)×(Wt)^(θ_7)(θ_1=0.18;θ_2=-0.19;θ_3=-0.31;θ_4=20.85;θ_5=-0.52;θ_6=-0.23;θ_7=0.98)。最终模型对应的CL和Vd群体典型值分别为5.0 L·h^(-1)和66.9 L,外部验证中贝叶斯预测平均误差分别为0.8 L·h^(-1)和9 L。结论本研究通过所建立的万古霉素PPK模型,较好的反应出中国成年患者的万古霉素PPK特征,贝叶斯单点反馈误差较低,为提高治疗效果、减少不良反应以及实现个体化给药提供了重要的理论实验参考依据。OBJECTIVE To design a individualized dosage regimen depend on the individual pharmacokinetic parameters which was calculated using the Byes feedback model and the constructed population pharmacokinetic（PPK） modle with the single point trough concentration of vancomycin. And the vancomycin PPK were established by using the sparse TDM datas from the adult patients treated with vancomycin in the 3 hospital of grace medical center. METHODS In the present paper, the concentration of 235 serum samples collected from 128 vancomycin treated patients were determined. One compartment pharmacokinetic model of intravenous injection integrated in Kinetica software was used for fitting the basic model by the calculating modle of maximum likelihood（EM） and Bayesian（Bayes）. Forward stepwise regression was used to study the relationships between the pharmacokinetic parameters（elimination rate constant, Kel; the apparent volume of distribution, Vd） and the covariants（serum creatinine, Scr; Age; Weight, Wt; Sex; Drug combination） and then fitted the final modle given the the fixed effect model by EM and Bayes again. In the end, the model was evaluated using the method of internal bootstrap and external validation method. RESULTS The final PPK modle in the current study was Kel=θ1×（Scr）^（θ2）×（Sex）^（θ3）, V=θ4×（Scr）^（θ5）×（Age）^（θ6）×（Wt）^（θ7）（θ1=0.18; θ2=-0.19; θ3=-0.31; θ4=20.85; θ5=-0.52; θ6=-0.23; θ7=0.98）. The population pharmacokinetic parameters（Cl and Vd） according to the final model were 5.0 L·h^-1 and 66.9 L, the Bayes predict error were 0.8 L·h^-1 and 9 L. CONCLUSION The established model of vancomycin PKK model can well reflect the population pharmacokinetic characteristics of Chinese adult vancomycin treated patients with low predicted error of the single point Byes feedback and provide the theoretical and practical basis for improving treating efficacy and reducing adverse reactions.

关 键 词：Kinetica 万古霉素 群体药动学 肌酐 

分 类 号：R969.1[医药卫生—药理学]