窄治疗指数药物利伐沙班片在中国健康受试者中的生物等效性研究  

Bioequivalence of narrow therapeutic index drug rivaroxaban tablets in Chinese healthy volunteers

作　　者：王铸辉 阳晓燕[2] 张行飞 阳国平[2] 黄洁[2] 邹婵[2] WANG Zhu-hui;YANG Xiao-yan;ZHANG Xing-fei;YANG Guo-ping;HUANG Jie;ZOU Chan(Hunan Center for Drug Evaluation and Adverse Reaction Monitoring,Changsha 410013;Clinical Trial Research Center,the Third Xiangya Hospital of Central South University,Changsha 410013)

机构地区：[1]湖南省药品审评与不良反应监测中心,长沙410013 [2]中南大学湘雅三医院临床试验研究中心,长沙410013

出　　处：《中南药学》2022年第8期1781-1786,共6页Central South Pharmacy

摘　　要：目的按窄治疗指数药物标准评价利伐沙班片受试制剂T与参比制剂R在中国成年健康受试者中的生物等效性。方法空腹和餐后各入组28例健康受试者,采用单中心、随机、开放、两制剂、四周期全重复交叉设计,受试者口服单剂量利伐沙班片受试制剂T和参比制剂R 20 mg。采用液相色谱串联质谱(LC-MS/MS)法测定血浆中利伐沙班的浓度,采用WinNonlin 8.0程序数据统计软件按非房室模型计算药动学参数,按窄治疗指数药物标准进行生物等效性评价。结果受试者口服20 mg受试制剂T和参比制剂R后,主要药动学参数如下:空腹组C_(max)分别为(195.28±46.01)、(197.48±52.63)ng·mL^(-1);AUC_(0~t)分别为(1490.58±356.92)、(1439.72±372.20)h·ng·mL^(-1);AUC_(0~∞)分别为(1609.00±394.74)、(1538.39±386.49)h·ng·mL^(-1)。餐后组C_(max)分别为(402.05±85.67)、(394.42±65.29)ng·mL^(-1);AUC_(0~t)分别为(2776.66±756.91)、(2728.24±801.16)h·ng·mL^(-1);AUC_(0~∞)分别为(2801.41±755.55)、(2760.30±805.05)h·ng·mL^(-1)。两种制剂的C_(max)、AUC_(0~t)和AUC_(0~∞)经对数转换后空腹组90%CI分别为94.73%~105.71%、97.55%~110.44%和97.81%~111.66%,个体内标准差比值90%CI上限分别为1.60、1.42和1.45;餐后组90%CI分别为96.84%~105.84%、96.09%~108.29%和95.89%~107.87%,个体内标准差比值90%CI上限分别为1.98、1.30和1.31,符合窄治疗指数药物生物等效性评判的标准。结论利伐沙班片受试制剂T与参比制剂R在空腹和餐后状态下均具有生物等效性。Objective To evaluate the bioequivalence of two rivaroxaban tablets with narrow therapeutic index in Chinese healthy volunteers.Methods Twenty-eight healthy volunteers were respectively recruited in fasting and fed.Single-center,single-dose,open,randomized,and four cycle fully repeated crossover design was used.A single oral dose of rivaroxaban tablets included the test preparation T and the reference preparation R 20 mg each.The concentrations of rivaroxaban in the plasma were determined by LC-MS/MS method.The pharmacokinetic parameters were calculated.The bioequivalence was determined by non-compartment model with WinNonlin(Vision 8.0)and evaluated with according to narrow therapeutic index drug criteria.Results The main pharmacokinetic parameters of a single oral rivaroxaban tablets(20 mg)under fasting condition for test preparation T and reference preparation R were as follows:C_(max) was(195.28±46.01)and(197.48±52.63)ng·mL^(-1);AUC_(0~t) was(1490.58±356.92)and(1439.72±372.20)h·ng·mL^(-1);AUC_(0~∞) was(1609.00±394.74)and(1538.39±386.49)h·ng·mL^(-1).The main pharmacokinetic parameters of a single oral rivaroxaban tablets(20 mg)under fed condition for test preparation T and reference preparation R were as follows:C_(max) was(402.05±85.67)and(394.42±65.29)ng·mL^(-1);AUC_(0~t) was(2776.66±756.91)and(2728.24±801.16)h·ng·mL^(-1);AUC_(0~∞)was(2801.41±755.55)and(2760.30±805.05)h·ng·mL^(-1).The 90%CI for the geometric mean ratios of C_(max),AUC_(0~t) and AUC_(0~∞) of test preparation T and reference preparation R under fasting condition was 94.73%~105.71%,97.55%~110.44%,and 97.81%~111.66%,respectively.The 90%CI upper for the limit for intra-individual standard deviation ratio was 1.60,1.42 and 1.45.The 90%CI for the geometric mean ratios of C_(max),AUC_(0~t) and AUC_(0~∞)of T and R under fed condition was 96.84%~105.84%,96.09%~108.29%,and 95.89%~107.87%,respectively.The 90%CI upper for the limit for intra-individual standard deviation ratio was 1.98,1.30 and 1.31,all of which met the crit

关 键 词：利伐沙班片 生物利用度 生物等效性 窄治疗指数药物 

分 类 号：R96[医药卫生—药理学]