盐酸二甲双胍缓释片的人体生物等效性研究  

Bioequivalence study of Metformin Hydrochloride Extended-Release Tablets under fasting and fed conditions in healthy subjects

作　　者：胡朝英 郜丹 宋岩[1] 李想 李林[1] 唐洋明 李庆洋 张兰[1] HU Chaoying;GAO Dan;SONG Yan;LI Xiang;LI Lin;TANG Yangming;LI Qingyang;ZHANG Lan(Department of Pharmacy,Phase I Clinical Trial Center,Xuanwu Hospital Capital Medical University,National Clinical Research Center for Geriatric Diseases,Beijing 100053,China;Hybio Pharmaceutical Co.,Ltd,Shenzhen 518057,China)

机构地区：[1]首都医科大学宣武医院药学部,Ⅰ期临床研究中心,国家老年疾病临床医学研究中心,北京100053 [2]深圳瀚宇药业有限公司,广东深圳518057

出　　处：《药物评价研究》2022年第1期78-83,共6页Drug Evaluation Research

基　　金：国家“重大新药创制”科技重大专项(2017ZX09101001-002-044);北京市医院管理中心“登峰”计划专项经费资助项目(DFL20190803);首都科技领军人才项目(Z191100006119017)。

摘　　要：目的评价中国健康受试者空腹和餐后状态下单次口服盐酸二甲双胍缓释片的生物等效性。方法采用单剂量、随机、开放、两制剂、两周期、交叉对照的试验设计,健康受试者每周期在空腹或餐后状态下口服盐酸二甲双胍缓释片受试制剂和参比制剂500 mg。采用经验证的液相色谱-串联质谱(LC-MS/MS)法测定二甲双胍的血浆浓度,使用Phoenix WinNonlin 8.0计算药动学参数并用SAS 9.4软件进行生物等效性评价。结果空腹状态下,受试制剂和参比制剂中二甲双胍C_(max)分别为(733.00±178.25)、(665.80±146.58)ng·mL^(−1),AUC_(0~t)分别为(4848.60±1204.80)、(4743.00±1104.34)h·ng·mL^(−1),AUC_(0~∞)分别为(4940.70±1219.48)、(4832.58±1093.55)h·ng·mL^(−1)。餐后状态下,受试制剂和参比制剂中二甲双胍C_(max)分别为(519.10±92.55)、(475.50±65.88)ng·mL^(−1),AUC_(0~t)分别为(5989.20±1112.01)、(5946.50±1094.81)h·ng·mL^(−1),AUC_(0~∞)分别为(6052.20±1118.35)、(6049.80±1062.28)h·ng·mL^(−1)。受试制剂和参比制剂二甲双胍C_(max)、AUC_(0~t)和AUC_(0~∞)几何均值比的90%置信区间均在80.00%~125.00%的生物等效性范围内。结论盐酸二甲双胍缓释片受试制剂和参比制剂在空腹和餐后状态下均具有生物等效性。Objective To evaluate the pharmacokinetics and bioequivalence of Metformin Hydrochloride Extended-Release Tablets under fasting and fed conditions in Chinese healthy subjects.Methods This was a randomized,open-label,double-sequence,twoperiod,crossover designed study,and healthy subjects enrolled and administrated a single dose of 500 mg test and reference Metformin Hydrochloride Extended-Release Tablets in each period under fasting or fed condition.The plasma concentrations of metformin were determined by a validated LC-MS/MS method.The pharmacokinetic parameters were calculated with WinNonlin 8.0 and the bioequivalence was evaluated through SAS 9.4 software.Results In the fasting condition,the major pharmacokinetic parameters of metformin of test and reference formulations were as follows,C_(max) were(733.0±178.25)and(665.8±146.58)ng·mL^(−1),AUC_(0-t) were(4848.60±1204.80)and(4743.00±1104.34)h·ng·mL^(−1),AUC_(0-∞)were(4940.70±1219.48)and(4832.60±1093.55)h·ng·mL^(−1),respectively.Subjects administrated test and reference formulations in fed condition had C_(max) of(519.10±92.55)and(475.50±65.88)ng·mL^(−1),AUC_(0-t) of(5989.20±1112.01)and(5946.50±1094.81)h·ng·mL^(−1),AUC_(0-∞)of(6052.20±1118.35)and(6049.80±1062.28)h·ng·mL^(−1),respectively.The 90%confidence intervals of geometric mean ratios were all within the bioequivalence range of 80.00%—125.00%.Conclusion The test formulation of Metformin Hydrochloride Extended-Release Tablets was bioequivalent to the reference product both under fasting and fed conditions.

关 键 词：盐酸二甲双胍缓释片 生物等效性 药动学 LC-MS/MS 

分 类 号：R969.1[医药卫生—药理学]