左旋多巴中国人群药动学模型的建立  

Population pharmacokinetic modeling of levodopa

作　　者：林玮玮[1] 王长连[1] 林翠鸿[1] 郭仙忠[1] 黄品芳[1] 刘亦伟[1] 吴钢[2] 

机构地区：[1]福建医科大学附属第一医院药学部,福建福州350005 [2]福建医科大学附属第一医院神经内科,福建福州350005

出　　处：《中国医院药学杂志》2012年第12期907-911,共5页Chinese Journal of Hospital Pharmacy

基　　金：福建省教育厅课题(编号:JA07102);福建省自然基金课题(编号:2009J01136)

摘　　要：目的:建立中国人群左旋多巴/苄丝肼复合制剂中左旋多巴的群体药动学模型。方法:前瞻性收集服用多巴丝肼片的帕金森病(PD)门诊患者稳态谷浓度97例102个血样和健康志愿者13例153个密集血样,高效液相色谱-电化学(HPLC-ECD)法测定左旋多巴(LD)血药浓度。应用NONMEM软件进行群体药动学数据分析,Bootstrap重复抽样用于模型的内部验证。另收集20例PD患者22个血样点作为验证组进行模型外部验证,计算最简模型和最终模型对验证组的平均预测误差(MPE)和平均绝对误差(MAE)对模型进行外部验证。结果:数据采用一房室模型拟合,年龄(AGE)对LD清除率有显著影响,性别(SEX)、体质量(WT)、给药剂量(TAMT)、合并用药不影响LD的药动学参数。LD的基础模型为:CL(CL/F)(L.h-1)=18.2×EXP[ETA(1)],V(V/F)(L)=48.4,ka(h-1)=2.13×EXP[ETA(2)];最终模型为:CL(CL/F)(L.h-1)=17.9×(55/AGE)0.59×(EXP[ETA(1)],V(V/F)(L)=47.5,ka(h-1)=2.14×EXP[ETA(2)]。CL、V、ka的群体典型值分别为17.9 L.h-1、47.5 L、2.14 h-1。Bootstrap重复抽样显示所建立的最终模型稳定、可靠,最终模型对验证组的MPE和MAE较最简模型有显著改善,显示模型有效,且有一定代表性。结论:根据患者的生理用药资料,结合上述模型,可估算个体药动学参数,为临床个体化给药提供参考。OBJECTIVE To establish a population pharmacokinetic model for levodopa（LD） in levodopa-benserazide com pound preparation. METHODS 102 eases of steady state serum concentration data and 153 dense serum concentration data were collected respectively from 97 PD outpatients and 13 healthy volunteers receiving levodopa-benserazide compound prepara tion orally. The plasma concentrations of levodopa（LD） was determined by HPI.C-ECD method, Population pharmacokinetic data analysis was performed using NONMEM software. The Bootstrap assay was applied for internal validation. 22 blood sam ples from 20 patients receiving levodop-benserazide compound preparation consisted validation group, MPE（mean prediction error） and MAE（mean absolute error） for validation group in simple and final model were calculated for external validation. RESULTS The data of LD corresponded with one compartment model. Age had conspicuous effect on clearance, while sex, weight, daily dose of administration, drug combination had no marked effect on pharrnacokinetic parameter of LD. The basic model was described as follows.. CL（L·h -1） = 18.2 EXP[ETA（1）],V（L） = 48.4, ko （h-1） = 2. 13 EXP[ETA（2）];The final model was described as follows：CL（L·h-1 ） = 17.9×（55/AGE）0.59× （EXP[ETA（1）] ,V（L） = 47.5 ,k, （h-1 ） = 2. 14×EXP [ETA（2）]. The population typical value of CL, V, kα were 17.9 L.h-1, 47.5 L, 2. 14 h -1. The measure of Bootstrap showed the final model was stable and reliable, MPE and MAE of validation group in final model were improved significantly comparing with simple model, which demonstrated that the final model was effective and predictive. CONCLUSION A novel population pharmacokinetic model was developed to estimate the individual pharmacokinetic parameter for patients receiving levodopa-benserazide compound preparation in terms of patients~ characteristics and dosing history, and to design a prior dosage regimen.

关 键 词：左旋多巴 群体药动学 非线性混合效应模型 

分 类 号：R969.1[医药卫生—药理学]