头孢氨苄胶囊在健康受试者中的生物等效性和药动学/药效学研究  

Bioequivalence and pharmacokinetic/pharmacodynamic study of cefalexin capsules in healthy subjects

作　　者：金逸 胡盈盈 郁继诚[1] 陈渊成[1] 戴静怡 王晶晶[1] 张菁[1] 武晓捷[1] 程洁如 丁玲玲 刘晓雪 龚玉秀 JIN Yi;HU Yingying;YU Jicheng;CHEN Yuancheng;DAI Jingyi;WANG Jingjing;ZHANG Jing;WU Xiaojie;CHENG Jieru;DING Lingling;LIU Xiaoxue;GONG Yuxiu(Phase I Clinical Laboratory,Huashan Hospital,Fudan University,Shanghai 200040,China)

机构地区：[1]复旦大学附属华山医院Ⅰ期临床研究室,上海200040 [2]上海上药新亚药业有限公司 [3]上海新亚药业闵行有限公司

出　　处：《中国感染与化疗杂志》2021年第4期432-437,共6页Chinese Journal of Infection and Chemotherapy

基　　金：科技部“重大新药创制”科技重大专项(“十三五”)(2017ZX09304005);上海市科委医学引导类科技支撑项目(17411961600);上海市科委产学研医项目(17DZ1910402);上海市高水平地方高校复旦大学上海医学院临床药学与监管科学重点创新团队建设项目(HJW-R-2019-66-19)。

摘　　要：目的研究头孢氨苄胶囊国产制剂与原研制剂在中国健康受试者中的生物等效性,并进行药动学/药效学(PK/PD)分析评价给药方案。方法采用单中心、随机、开放、单剂量、两周期、两交叉、空腹或餐后给药试验设计。入选研究受试者56名按照1∶1的比例随机进入2个试验组,一组受试者按照方案规定先后给予受试制剂-参比制剂,另一组则参比制剂-受试制剂,两周期自身交叉,空腹给药或高脂餐后给药,并按设计的时间点采集血样。采用LC-MS/MS法测定血浆中头孢氨苄浓度。采用WinNonlin软件计算药动学参数,并对主要药动学参数进行生物等效性评价。采用单点法计算头孢氨苄不同给药方案的%T>MIC以及%T>MIC(靶值=40%)达标概率(PTA),优化给药方案。结果空腹或餐后给药后,受试制剂和参比制剂组的药时曲线和药动学参数均相似。空腹状态下参比制剂组的C_(max)、AUC_(0-∞)分别为5.64 mg/L、8.99 h·mg/L,受试制剂组分别为6.02 mg/L、9.12 h·mg/L。餐后状态下参比制剂C_(max)、AUC_(0-∞)分别为2.51 mg/L、8.04 h·mg/L;受试制剂分别为2.60mg/L、8.22 h·mg/L。空腹组主要药动力学参数C_(max)、AUC_(0-∞)几何均值比(受试制剂/参比制剂)分别为106.91%(101.45%~112.66%)、101.22%(99.14%~103.34%),餐后组分别为102.29%(94.41%~110.84%)、102.08%(100.24%~103.95%)。头孢氨苄C_(max)、AUC_(0-∞)几何均值比值90%置信区间均落在80.00%~125.00%范围内。空腹给予头孢氨苄250、500、1000 mg(均为1次/6 h给药),当该药对致病菌MIC为0.5、1、2 mg/L时,预期达到PTA均高于90%。结论餐后和空腹给予头孢氨苄受试制剂与参比制剂生物等效。临床治疗敏感病原菌引起的感染采用250~500 mg(1次/6 h)给药方案预期可获得较好微生物疗效。Objective To study the bioequivalence between domestic cefalexin capsule and the original preparation in healthy Chinese subjects,and evaluate the dosing regimen based on PK/PD analysis.Methods This trial was designed as a single-center,randomized,open-label,single-dose,two-cycle,two-cross,dosing under fasted or fed condition.Plasma cefalexin concentration was determined by LC-MS/MS.The enrolled subjects(n=56)were randomized to a group to receive test preparation followed by reference preparation or to the other group to receive reference preparation followed by test preparation in a ratio of 1:1.WinNonlin software was used to calculate the PK parameters.The bioequivalence of the key PK parameters was evaluated.Single point method was used to calculate the%T>MIC of different dosing regimens of cefalexin,as well as the probability of%T>MIC reaching the target value(target value=40%)to optimize the regimens.Results After administration under fasted or fed condition,the test preparation and reference preparation showed similar concentration-time curves and PK parameters.C_(max) and AUC_(0-∞) were 5.64 mg/L and 8.99 h·mg/L respectively for the reference preparation;6.02 mg/L and 9.12 h·mg/L respectively for the test preparation,under fasted condition.C_(max) and AUC_(0-∞) were 2.51 mg/L and 8.04 h·mg/L respectively for the reference preparation;2.60 mg/L and 8.22 h·mg/L respectively for the test preparation,under fed condition.The geometric mean ratios(T/R)of key PK parameters C_(max) and AUC_(0-∞) were 106.91%(101.45%-112.66%)and 101.22%(99.14%-103.34%)in the fasting group;102.29%(94.41%-110.84%)and 102.08%(100.24%-103.95%)in the postprandial group,respectively.The 90%confidence intervals of cefalexin C_(max) and AUC_(0-∞) geometric mean ratios all fell within the range of 80.00%-125.00%.When the drug MIC against pathogenic bacteria was 0.5 mg/L,1 mg/L,2 mg/L,it is expected that administration of cephalexin 250 mg,500 mg,1000 mg(q6h)under fasted condition can attain the desired probability of target atta

关 键 词：头孢氨苄 健康受试者 生物等效性 药动学/药效学 

分 类 号：R978.11[医药卫生—药品]