盐酸乙胺丁醇片在中国健康受试者体内的生物等效性研究  

Bioequivalence study of ethambutol hydrochloride tablets in healthy Chinese subjects

作　　者：陈红英 付喜花 古文钊 杨辉 潘碧妍 姜金生 欧阳冬生[1,4] CHEN Hong-ying;FU Xi-hua;GU Wen-zhao;YANG hui;PAN Bi-yan;JIANG Jin-sheng;OUYANG Dong-sheng(Department of Clinical Pharmacology,Xiangya Hospital,Central South University,Changsha 410000,Hunan Province,China;Guangzhou Baiyunshan Mingxing pharmaceutical Co.Ltd,Guangzhou 510250,Guangdong Province,China;Infectious Disease Department,Guangzhou Panyu District Central Hospital,Guangzhou 510000,Guangdong Province,China;Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples,Changsha 410000,Hunan Province,China)

机构地区：[1]中南大学湘雅医院临床药理研究所,湖南长沙410000 [2]广州白云山明兴制药有限公司,广东广州510250 [3]广州市番禺区中心医院感染科,广东广州510000 [4]复杂基质样本生物分析湖南省重点实验室,湖南长沙410000

出　　处：《中国临床药理学杂志》2022年第22期2746-2750,共5页The Chinese Journal of Clinical Pharmacology

基　　金：湖南省复杂基质样本生物分析国际科技创新合作基地基金资助项目(2019CB1014);湖南省重点领域研发计划-药物临床评价关键技术创新及应用示范基金资助项目(2019SK2241);广州市科技计划-基于药物一致性评价流程化服务平台的广州市药物重点攻关基金资助项目(201604046024);广州市民生科技攻关计划民生科技攻关专题基金资助项目(20193010016)。

摘　　要：目的评价盐酸乙胺丁醇片受试制剂和参比制剂在中国健康受试者的生物等效性及安全性。方法采用单中心、随机、开放、单剂量、两周期、双交叉试验设计。空腹试验纳入48例受试者,餐后试验纳入24例受试者,每周期单次空腹或餐后口服受试制剂或参比制剂0.25 g。按不同的时间点采静脉血,用液相色谱串联质谱法测定受试者血浆中乙胺丁醇的浓度,用Phoenix WinNonlin 8.0和SAS(9.4)计算药代动力学参数,分析两种制剂的生物等效性。结果空腹口服盐酸乙胺丁醇受试制剂和参比制剂后的主要药代动力学参数:C_(max)分别为(8.43±2.72)×10^(2)和(8.49±3.27)×10^(2) ng·mL^(-1);AUC_(0-t)分别为(5.40±0.95)×10^(3)和(5.39±0.97)×10^(3) ng·h·mL^(-1);AUC_(0-∞)分别为(5.80±0.97)×10^(3)和(5.78±1.01)×10^(3) ng·h·mL^(-1)。餐后口服盐酸乙胺丁醇受试制剂和参比制剂后的主要药代动力学参数:C_(max)分别为(7.98±2.37)×10^(2)和(8.18±2.26)×10^(2) ng·mL^(-1);AUC_(0-t)分别为(5.02±0.64)×10^(3)和(5.01±0.50)×10^(3) ng·h·mL^(-1);AUC_(0-∞)分别为(5.36±0.69)×10^(3)和(5.34±0.51)×10^(3) ng·h·mL^(-1)。C_(max)、AUC_(0-t)和AUC_(0-∞)的几何均数比值(受试制剂/参比制剂)的90%置信区间统计结果均在80.00%~125.00%内。试验过程中空腹组和餐后组不良事件发生率分别为27.08%(13例/48例)和54.17%(13例/24例),试验过程均无严重不良事件和非预期不良事件发生。结论两种盐酸乙胺丁醇片在中国健康受试者单次空腹和餐后给药条件下具有生物等效性,且安全性良好。Objective To evaluate the bioequivalence and safety of ethambutol hydrochloride tablets preparations and reference preparations in healthy Chinese subjects.Methods The study is a single center,randomized,open,single-dose,two-cycle,double-crossover design.The fasting trial included 48 subjects,and the fed trial included 24 subjects.0.25 g of the test preparation or reference preparation was orally taken on a fasting or postprandial condition once per cycle.Blood samples were collected at different time points.Blood concentration of ethambutol was determined by LC-MS/MS method and pharmacokinetic parameters were calculated by Phoenix WinNolin(version 8.0)and SAS(version 9.4)software to perform the bioequivalence evaluation of the two preparations.Results The main pharmacokinetic parameters of the test and reference preparations after a single oral administration of ethambutol hydrochloride in fasting condition:C_(max) were(8.43±2.72)×10^(2) and(8.49±3.27)×10^(2) ng·mL^(-1);AUC_(0-t) were(5.40±0.95)×10^(3) and(5.39±0.97)×10^(3) ng·h·mL^(-1);AUC_(0-∞)were(5.80±0.97)×10^(3) and(5.78±1.01)×10^(3) ng·h·mL^(-1).The main pharmacokinetic parameters of the test and reference preparations after a single oral administration of ethambutol hydrochloride in fed condition:C_(max) were(7.98±2.37)×10^(2) and(8.18±2.26)×10^(2) ng·mL^(-1);AUC_(0-t) were(5.02±0.64)×10^(3) and(5.01±0.50)×10^(3) ng·h·mL^(-1);AUC_(0-∞)were(5.36±0.69)×10^(3) and(5.34±0.51)×10^(3) ng·h·mL^(-1).The 90%confidence interval statistics of the C_(max),AUC_(0-t),AUC_(0-∞)geometric mean ratio(test/reference preparation)was in the 80.00%-125.00%range.The incidence of adverse events in fasting and fed conditions were 27.08%(13 cases/48 cases)and 54.17%(13 cases/24 cases)respectively;there were no serious adverse events and unexpected adverse events during the trial.Conclusion Two kinds of ethambutol hydrochloride tablets were bioequivalent and well safe under fasting and fed administrations.

关 键 词：盐酸乙胺丁醇片 药代动力学 生物等效性 液相色谱-串联质谱法 

分 类 号：R969.4[医药卫生—药理学]