利伐沙班片在健康中国人中的药动学研究和生物等效性评价  

Pharmacokinetics study and bioequivalence evaluation of Rivaroxaban Tablets in Chinese healthy subjects

作　　者：刘欢[1] 池慧波 侯珏卓[1] 张荣蓉 朱建强[1] LIU Huan;CHI Huibo;HOU Juezhuo;ZHANG Rongrong;ZHU Jianqiang(Technology R&D Center,TIPR Pharmaceutical Co.,Ltd.,Tianjin 300301,China;Shijiazhuang Yanshi Hengyue Medical Technology Co.,Ltd.,Shijiazhuang 050051,China)

机构地区：[1]天津药物研究院药业有限责任公司,天津300301 [2]石家庄研实恒越医药科技有限公司,河北石家庄050051

出　　处：《药物评价研究》2024年第1期115-122,共8页Drug Evaluation Research

摘　　要：目的 研究利伐沙班片(规格:2.5 mg)在健康中国人中的药动学特征,并对其与参比制剂的生物等效性进行评价。方法 70例健康受试者口服2.5 mg利伐沙班受试制剂和参比制剂(拜瑞妥■),采用开放、单剂量、随机、完全重复、四周期交叉设计,分为单次空腹给药试验(42例)和单次餐后口服给药试验(28例)两部分,用液相色谱-质谱联用法测定服药后48 h内18个不同时间点的血药浓度,计算主要药动学参数。采用方差分析、双单侧t检验和90%置信区间(90CI)分析进行两制剂生物等效性评价。结果 受试者空腹状态下口服受试制剂和参比制剂后,主要药动学参数血浆药物最大浓度(C_(max))、血浆半衰期(t_(1/2))、药时曲线下面积(AUC_(0~t))分别为(66.3±18.4)ng·mL^(-1)、(4.76±1.73)h、(323.9±98.4)h·ng·mL^(-1)和(64.5±17.6)ng·mL^(-1)、(4.45±1.47)h、(321.3±104.5)h·ng·mL^(-1)。受试者高脂餐后状态下口服受试制剂和参比制剂后,主要药动学参数C_(max)、 t_(1/2)和AUC_(0~t)分别为(59.5±13.3) ng·mL^(-1)、(5.14±1.24) h、(341.7±70.8) h·ng·mL^(-1)和(60.5±10.7) ng·mL^(-1)、(5.29±1.56)h、(348.8±77.6)h·ng·mL^(-1)。C_(max)、AUC_(0~t)、AUC_(0~∞)的几何平均数比值(GMR)的90CI均落在80.00%~125.00%内,个体内标准差比值(SWT/SWR)的90%CI上限均不超过2.5,表明受试制剂中利伐沙班的吸收程度、吸收速率及在个体内的变异与参比制剂具有生物等效性。结论 采用LC-MS/MS方法测定人血浆中利伐沙班含量,在中国健康受试者中利伐沙班(2.5 mg)受试制剂与参比制剂在空腹及高脂餐后给药具有生物等效性。Objective To study the pharmacokinetics of 2.5 mg Rivaroxaban Tablets in Chinese healthy subjects and evaluate the bioequivalence to the reference reagent.Methods 70 healthy subjects were administered oral 2.5 mg rivaroxaban test agent and reference reagent(Xarelto®).An open,single-dose,random,completely repeated and four-cycle crossover design was adopted.The subjects were divided into two groups,which are a single administration of the test(42 subjects)under fasting state and a single postprandial oral administration of the test(28 subjects).To calculate the main drug parameters,the LC-MS/MS was applied to determine the blood drug concentration at 18 different time points within 48 h after administration of the preparations.Bioequivalence was evaluated by using analysis of variance,two-sided one-sided t test,and 90%confidence interval analysis.Results After oral administration of test and reference preparation in fasting state,the main pharmacokinetic parameters C_(max),t_(1/2) and AUC_(0~t) are(66.3±18.4)ng·mL^(−1),(4.76±1.73)h,(323.9±98.4)h·ng·mL^(−1) and(64.5±17.6)ng·mL^(−1),(4.45±1.47)h,(321.3±104.5)h·ng·mL^(−1).The main pharmacokinetic parameters of C_(max),t_(1/2) and AUC_(0~t) after oral administration of test and reference preparations after high-fat diet are(59.5±13.3)ng·mL^(−1),(5.14±1.24)h,(341.7±70.8)h·ng·mL^(−1) and(60.5±10.7)ng·mL^(−1),(5.29±1.56)h,(348.8±77.6)h·ng·mL^(−1).The geometric mean ratio points of C_(max),AUC_(0~t) and AUC_(0~∞)are between 80.00%to 125.00%,and the upper and lower limits of 90%confidence interval of variation rate within individuals were less than 2.5,the results indicated that the absorption degree,absorption rate and variation of rivaroxaban in test preparations were similar to reference preparations.Conclusion The LC-MS/MS method was used to determine the content of rivaroxaban in human plasma.The rivaroxaban(2.5 mg)test preparation and the reference preparation were bioequivalent when administered under fast state and after a

关 键 词：利伐沙班 液相色谱-质谱法 生物等效性 药动学 片剂 

分 类 号：R969.1[医药卫生—药理学]