目的 研究利伐沙班片（規(guī)格：2.5 mg）在健康中國人中的藥動學特征，并對其與參比制劑的生物等效性進行評價。方法 70例健康受試者口服2.5 mg利伐沙班受試制劑和參比制劑（拜瑞妥^®），采用開放、單劑量、隨機、完全重復、四周期交叉設(shè)計，分為單次空腹給藥試驗（42例）和單次餐后口服給藥試驗（28例）兩部分，用液相色譜-質(zhì)譜聯(lián)用法測定服藥后48 h內(nèi)18個不同時間點的血藥濃度，計算主要藥動學參數(shù)。采用方差分析、雙單側(cè)t檢驗和90%置信區(qū)間（90CI）分析進行兩制劑生物等效性評價。結(jié)果 受試者空腹狀態(tài)下口服受試制劑和參比制劑后，主要藥動學參數(shù)血漿藥物最大濃度（C_max）、血漿半衰期（t_1/2）、藥時曲線下面積（AUC_0～t）分別為（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。受試者高脂餐后狀態(tài)下口服受試制劑和參比制劑后，主要藥動學參數(shù)C_max、t_1/2和AUC_0~t分別為（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～∞的幾何平均數(shù)比值（GMR）的90CI均落在80.00%～125.00%內(nèi)，個體內(nèi)標準差比值（S_WT/S_WR）的90%CI上限均不超過2.5，表明受試制劑中利伐沙班的吸收程度、吸收速率及在個體內(nèi)的變異與參比制劑具有生物等效性。結(jié)論 采用LC-MS/MS方法測定人血漿中利伐沙班含量，在中國健康受試者中利伐沙班（2.5 mg）受試制劑與參比制劑在空腹及高脂餐后給藥具有生物等效性。

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 high-fat diet.

R969.1