利伐沙班在健康人体的药动学及生物等效性评价  

Pharmacokinetics and bioequivalence of rivaroxaban in healthy volunteers

作　　者：李丹[1] 王婷[1] 梁莉[1] 乔华[1] 常威[1] 高振月 吴科毅 LI Dan;WANG Ting;LIANG Li;QIAO Hua;CHANG Wei;GAO Zhen-yue;WU Ke-yi(The First Hospital of Lanzhou University,Lanzhou 730030,China;Zhengda Tianqing Pharmaceutical Group Co.,Ltd.,Nanjing 210006,China)

机构地区：[1]兰州大学第一医院,兰州730030 [2]正大天晴药业集团股份有限公司,南京210006

出　　处：《中国新药杂志》2021年第15期1401-1406,共6页Chinese Journal of New Drugs

摘　　要：目的:研究利伐沙班片在健康人体的药动学特征,并对2种制剂的生物等效性进行评价。方法:60例健康受试者口服利伐沙班受试试剂和参比试剂(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(30例)和单次餐后口服给药试验(30例)两部分,用液相色谱-质谱联用法测定服药后72 h内14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%置信区间分析进行生物等效性评价。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Cmax,t1/2和AUC0-72h分别为(186.38±51.46)ng·mL^(-1),(8.67±2.56)h,(1346.80±325.67)ng·h·mL^(-1)和(183.21±57.06)ng·mL^(-1),(8.42±2.67)h,(1308.91±293.86)ng·h·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Cmax,t1/2和AUC0-72h分别为(257.72±37.10)ng·mL^(-1),(5.04±0.71)h,(1929.80±292.45)ng·h·mL^(-1)和(257.52±40.29)ng·mL^(-1),(5.45±0.87)h,(1925.58±333.20)ng·h·mL^(-1)。Cmax,AUC0-t,AUC0-∞的几何均值比点估计均落在80.00%~125.00%之间,且个体内变异比率90%置信区间上限值均≤2.5,表明利伐沙班片受试制剂与参比制剂具有生物等效性。结论:本研究采用LC-MS/MS方法测定人血浆中利伐沙班含量,利伐沙班受试制剂与参比制剂在空腹及高脂餐后给药时具有生物等效性。Objective:To study the pharmacokinetics of rivaroxaban tablets in healthy subjects and to evaluate the bioequivalence of the 2 preparations.Methods:60 healthy subjects were administered oral rivaroxaban test agent and reference reagent(Xarelto^(R)).An open,single-dose,random,completely repeated,four-cycle crossover design was adopted.The subjects were divided 2 groups,such as a single administration ofthe test(30 subjects)under fasting state and a single postprandial oral administration of the test(30 subjects).The liquid chromatography-mass spectrometry was applied to determine the blood drug concentration at 14 different time points within 72 h after administration of the preparations,and the main drug parameters were calculated.Bioequivalence was evaluated 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 Cmax,t1/2 and AUC0-72 h are(186.38±51.46)ng·mL^(-1),(8.67±2.56)h,(1346.80±325.67)ng·h·mL^(-1) and(183.21±57.06)ng·mL^(-1),(8.42±2.67)h,(1308.91±293.86)ng·h·mL^(-1).The main pharmacokinetic parameters of Cmax,t1/2 and AUC0-72 h after oral administration of test and reference preparations after high-fat diet are(257.72±37.10)ng·mL^(-1),(5.04±0.71)h,(1929.80±292.45)ng·h·mL^(-1) and(257.52±40.29)ng·mL^(-1),(5.45±0.87)h,(1925.58±333.20)ng·h·mL^(-1).The geometric mean ratio points of Cmax,AUC0-t,and AUC0-∞are between 80.00%and 125.00%,and the 90%confidence interval upper limit values of the intra-individual variation ratio are all≤2.5,indicating that the test rivaroxa tablet and the reference preparation are bioequivalent.Conclusion:In this study,the LC-MS/MS method was used to determine the content of rivaroxaban in human plasma.The rivaroxaban test preparation and the reference preparation were bioequivalent when administered under fast state and after a high-fat diet.

关 键 词：利伐沙班 液相色谱-质谱联用 生物等效性 

分 类 号：R969.1[医药卫生—药理学] R973.2[医药卫生—药学]