基于PK-PD研究确定头孢曲松舒巴坦Ⅱ期临床给药方案  

Use of preclinical and phaseⅠ data for determining a phaseⅡ dose for ceftriaxone/sulbactam injection

作　　者：李苌清 陈昭丽[2] 王广基[3] 王霆 

机构地区：[1]广州威尔曼新药研发有限公司,广东广州510075 [2]中南大学药学院药物分析教研室,湖南长沙410013 [3]中国药科大学,江苏南京210094 [4]湘北威尔曼制药有限公司,湖南长沙410329

出　　处：《现代医药卫生》2011年第2期188-190,共3页Journal of Modern Medicine & Health

摘　　要：目的:基于临床前药效学(PD)和I期临床药动学(PK)资料,进行给药方案的Monte Carlo模拟,确定头孢曲松钠舒巴坦钠(2:1)Ⅱ期临床试验的给药方案。方法:整理临床前的药敏实验、后抑效应和Ⅰ期临床药动学等PK-PD相关研究资料。以静脉滴注0.5～2.5 g/次(以头孢曲松量计),每日1次(Qd)、2次(Bid)、3次(Tid)等多种给药方案,治疗常见产ESBLs致病菌感染进行Monte Carlo模拟,将获得的累积反应分数(CFR)做给药方案的比较。结果:以CFR≥90%的给药方案为最佳给药方案。按Qd、Bid和Tid等不同频率给药,治疗常见产ESBLs致病菌感染所需的每次最低给药剂量分别为2.2 g、1.3 g和1.1 g。结论:从药物安全性、药代动力学同步性、以及成本效益角度考虑,头孢曲松钠舒巴坦钠(2:1)Ⅱ期临床试验的最佳给药方案是1.3 g Bid。Objective：To select a phaseⅡ dose for ceftriaxone/sulbactam injection by Monte Carlo simulation using the data of preclinical pharmacodynamics（PD） and the phaseⅠ pharmacokinetics（PK）.Methods：The pharmacodynamic data（MICs） were obtained from the preclinical studies.The pharmacokinetic data from the phase Ⅰ clinical research trials and published protein binding were varied according to log-normal and uniform distributions.A Monte Carlo simulation（10,000 subjects） estimated the probability of target attainment（PTA） and cumulative fraction of response（CFR） for drug concentrations at 50% T（MIC） for intravenous ceftriaxone 0.5-2.5g every 8-24 h.Resluts：With the dosage of CFR≥ 90% as the optimal dosage regimen,the lowest dosage for treating common infection caused by extended-spectrum β-lactamase-producing Enterobacteriaceae was 2.2g every 24h,1.3g every 12h and 1.1g every 8h respectively.Conclusion：The regimen of 1.3g every 12h is an appropriate dose for phaseⅡ of ceftriaxone/sulbactam injection,based on its PK/PD characteristics,safety and cost effect.

关 键 词：头孢曲松钠舒巴坦钠 MONTE CARLO模拟 药动学 药效学 

分 类 号：R9[医药卫生—药学]