基于PK/PD理论优化帕珠沙星在临床应用上的研究  

Study on the optimization of pazufloxacin in clinical application based on PK/PD theory

作　　者：李贺[1] 王哲欢 焦响乐 王瑞[3] 李晓天[2] 张晓坚[1] Li He;Wang Zhe-huan;Jiao Xiang-yue;Wang Rui;Li Xiao-tian;Zhang Xiao-jian(The First Affiliated Hospital of Zhengzhou University,Zhengzhou 450001;College of Pharmacy,Zhengzhou University,Zhengzhou 450001;Luohe Central Hospital,Luohe 462000)

机构地区：[1]郑州大学第一附属医院,郑州450001 [2]郑州大学药学院,郑州450001 [3]漯河市中心医院,漯河462000

出　　处：《中国抗生素杂志》2023年第4期453-457,共5页Chinese Journal of Antibiotics

基　　金：河南省科技公关资助项目(No.16210231540)。

摘　　要：目的基于药动/药效(pharmacokinetic/pharmacodynamic,PK/PD)理论,应用蒙特卡洛模拟(Monte Carlo simulation,MCS)评价及优化不同病原菌感染时帕珠沙星的给药方案。方法将12名健康志愿受试者分为3组,分别给予300、500和1000 mg3种不同剂量的帕珠沙星,以高效液相色谱法测得血药浓度,进而求出PK参数。用琼脂二倍稀释法确定大肠埃希菌、肺炎克雷伯菌、铜绿假单胞菌、金黄色葡萄球菌、表皮葡萄球菌和肺炎链球菌6种临床分离菌株物的最低抑菌浓度以进行PD研究。根据PK/PD研究结果,以AUC_(0-24)/MIC作为帕珠沙星的PK/PD指数(靶值为30、100和125),通过蒙特卡洛模拟得出不同给药方案的达标概率(probability of target attainment,PTA)和累积响应百分率(cumulative fraction of response,CFR),评价出最佳给药方案。结果以CFR>90%的给药方案作为临床最佳给药方案,蒙特卡洛模拟10000次的结果得出,帕珠沙星在1000 mg的给药剂量下对肺炎链球菌的CFR可达到92.33%,在500和1000 mg的给药剂量下对表皮葡萄球菌的CFR可达到90.11%和93.79%;对大肠埃希菌、肺炎克雷伯菌、金黄色葡萄球菌和铜绿假单胞菌的CFR均小于90%。结论在表皮葡萄球菌感染时推荐使用500 mg qd的帕珠沙星;在日剂量为1000 mg时帕珠沙星对肺炎链球菌的感染有很好的效果,对大肠埃希菌、肺炎克雷伯菌、金黄色葡萄球菌和铜绿假单胞菌的抑制效果不佳,可作为辅佐治疗药物。不同致病菌感染时所需要的给药剂量存在明显差异,根据PK/PD理论以及蒙特卡洛模拟可为帕珠沙星临床最佳给药方案的制定提供依据。Objective Based on the pharmacokinetic/pharmacodynamic(PK/PD)theory,Monte Carlo simulation was used to evaluate and optimize the dosing regimen of pazufloxacin for different pathogen infections.Methods Twelve healthy volunteers were divided into three groups and were given three different doses of pazufloxacin,low,medium,and high.The plasma concentration was measured by high performance liquid chromatography,and the PK parameters were calculated.The minimum inhibitory concentrations of six clinically isolated strains of Escherichia coli,Klebsiella pneumoniae,Pseudomonas aeruginosa,Staphylococcus aureus,Staphylococcus epidermidis,and Streptococcus pneumoniae were determined by the agar double dilution method for PD research.According to the results of the PK/PD study,AUC_(0-24)/MIC was used as the PK/PD index of pazufloxacin(target values were 30,100 and 125).Through Monte Carlo simulation,the probability of target attainment and the cumulative fraction of response of different dosing regimens were obtained to evaluate the best dosing regimen.Results With CFR>90%as the optimal dosage regimen of empirical therapy,the results of 10,000 Monte Carlo simulations showed that pazufloxacin had a CFR of 92.33%for Streptococcus pneumoniae at a dose of 1000 mg,and a CFR of 90.11%and 93.79%for Staphylococcus epidermidis at a dose of 500 and 1000 mg.The CFR of Escherichia coli,Klebsiella pneumoniae,Staphylococcus aureus,and Pseudomonas aeruginosa were all less than 90%.Conclusion It is recommended to use 500 mg qd pazufloxacin for Staphylococcus epidermidis infection;Pazufloxacin has a good effect on Streptococcus pneumoniae infection at a daily dose of 1000 mg.But it has poor inhibitory effects on Escherichia coli,Klebsiella pneumoniae,Staphylococcus aureus,and Pseudomonas aeruginosa,but can be used as an adjuvant therapy.There are significant differences in the dosage required for different pathogenic bacteria infections.The PK/PD theory and Monte Carlo simulation can provide a basis for the formulation of the best clinical

关 键 词：帕珠沙星 药动/药效 蒙特卡洛模拟 

分 类 号：R969.3[医药卫生—药理学]