去甲万古霉素群体药动学研究  

Population pharmacokinetics of norvancomycin

作　　者：张菁[1] 张婴元[1] 施耀国[1] 芮建中[2] 郁继诚[1] 曹国英[1] 吴菊芳[1] 

机构地区：[1]复旦大学附属华山医院抗生素研究所,上海200040 [2]南京军区南京总医院临床药理科

出　　处：《中国感染与化疗杂志》2007年第5期318-322,共5页Chinese Journal of Infection and Chemotherapy

基　　金：国家高技术研究发展计划(863计划)"抗感染药临床试验关键技术和平台研究"(编号:2002AA2Z341E)

摘　　要：目的研究去甲万古霉素在感染患者中的群体药动学(PPK)。方法PPK研究在诊断或拟诊为革兰阳性菌感染患者146例中进行,以非线性混合效应模型(NONMEM)程序建立并验证去甲万古霉素PPK模型,根据患者的PPK参数制定给药方案。结果①去甲万古霉素基础药动学模型为线性二房室模型,药动学参数个体间变异为指数模型,个体内变异为加法模型,清除率(CL)、中央室分布容积(V_1)、室间清除率(Q)和周边室分布容积(V_2)的患者个体间变异分别为35.92%、11.40%、0和79.75%,残差误差为3.05mg/L;②患者Ccr值的变化对去甲万古霉素CL的影响不同,当患者肾功能减退时(Ccr≤85 mL/min),CL=2.54×(Ccr/50)^(1.20),当患者肾功能正常时(Ccr>85mL/min),CL=5.66×(WT/60)^(0.52);③患者合并使用利尿药后使去甲万古霉素V_2增大;④老年感染患者(≥65岁)的CL减慢、t_(1/2β)延长,AUC增大。结论肾功能减退和年龄对去甲万古霉素药动学参数有显著影响;根据上述研究结果制定了去甲万古霉素在不同群体患者中的给药方案。Objective Population pharmcokinetics （PPK） of norvancomycin was investigated. Methods The studied dataset was from 146 patients diagnosed or suspected with gram-positive bacterial infection. A PPK model was established and validated using nonlinear mixed effect modeI（NONMEM） software after obtaining PPK parameters. Dosing regimens of norvancomycin were finally established. Results ①The best model was a two-compartment pharmacokinetic model with exponential interindividual error and additive residual error statistical models. Interindividual variability in CL, V1 , Q and V2 was 35.92 %, 11.40%, 0 and 79.75%, respectively. Residual variability was 3.05 mg/L. ②The finding in this study indicated that the change in Ccr value had different impacts on drug clearance （CL）. When patient had renal dysfunction （Ccr≤85 mL/min）, CL = 2. 54 × （Ccr〉50）^1.20. When the renal function was normal （Ccr〉85 mL/min）, CL = 6.0 × （WT/60）^0.52. ③The increased volume of peripheral distribution （V2） was observed when norvancomycin was co-administered with diuretics;④Reduced drug clearance, prolonged t1/2, and increased values of AUC24 were found in elderly patients. Conclusions Renal function impairment and age have significant impact on PK parameters of norvancomycin. Dosing regimens of norvancomycin were finally established for different patients on the basis of important PPK parameters generated from different groups of patients.

关 键 词：去甲万古霉素 群体药动学 非线性混合效应模型 治疗药物浓度监测 荧光偏振免疫法 

分 类 号：R96[医药卫生—药理学]