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

关键词:  Kinetica  万古霉素  群体药动学  肌酐

Key words:  Kinetica  vancomycin  population pharmacokinetic  creatinine

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=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）。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。

Abstract:

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.