阿齐沙坦氨氯地平片在健康受试者中的生物等效性研究

Bioequivalence of azilsartan amlodipine tablets in healthy subjects

关键词:  阿奇沙坦氨氯地平  生物等效性  LC-MS/MS  药代动力学

Key words:  azilsartan amlodipine  bioequivalence  LC-MS/MS  pharmacokinetic

摘要:

目的 评价阿齐沙坦氨氯地平片受试制剂和参比制剂在中国健康受试者中的生物等效性。方法 采用单中心、随机、开放、双周期、交叉、空腹/餐后状态下的试验设计,空腹组和餐后组各入组30例健康受试者,每周期口服阿齐沙坦氨氯地平片(每片含阿齐沙坦20 mg和氨氯地平5 mg)1片。采用高效液相色谱-串联质谱法(LC-MS/MS)测量给药后不同时间点血浆中阿齐沙坦和氨氯地平的血药浓度。选择Phoenix Win Nonlin7.0软件,以非房室模型计算主要药代动力学参数,使用SAS 9.4软件进行生物等效性评价。结果 空腹组受试制剂与参比制剂阿齐沙坦的主要药代动力学参数Cmax分别为(2306.67 ± 630.91)和(2364.00 ± 439.54)ng·mL-1,AUC0-t分别为(17390.72 ± 4664.15)和(16739.84 ± 3640.58)h·ng·mL-1,AUC0-∞分别为(17569.85 ± 4678.80)和(17109.88 ± 3739.18)h·ng·mL-1；氨氯地平Cmax分别为(3.59 ± 1.12)和(3.39 ± 0.89)ng·mL-1,AUC0-t分别为(164.89 ± 67.54)和(153.04 ± 50.05)h·ng·mL-1,AUC0-∞分别为(190.27 ± 88.10)和(182.39 ± 62.40)h·ng·mL-1。餐后组受试制剂与参比制剂阿齐沙坦的主要药代动力学参数Cmax分别为(2080.67 ± 451.72)和(2053.79 ± 424.14)ng·mL-1,AUC0-t 分别为(17081.63 ± 4409.54)和(16273.82 ± 3816.66)h·ng·mL-1,AUC0-∞分别为(17252.11 ± 4413.48)和(16440.06 ± 3828.30)h·ng·mL-1；氨氯地平Cmax分别为(3.30 ± 0.62)和(3.47 ± 0.72) ng·mL-1,AUC0-t 分别为(149.50 ± 37.24)和(147.90 ± 35.28)h·ng·mL-1,AUC0-∞分别为(174.22 ± 53.46)和(172.04 ± 49.55)h·ng·mL-1。受试制剂与参比制剂Cmax、AUC0-t和AUC0-∞几何均值比值的90%置信区间均在80.00% ~ 125.00%之间。结论 两种阿齐沙坦氨氯地平片在健康受试者中空腹和餐后状态下具有生物等效性。

Abstract:

Objective To evaluate the bioequivalence of azilsartan amlodipine tablets between test preparation and reference preparation in Chinese healthy subjects. Methods? A single-center, random, open, 2-period, double-crossover test is designed. The fasting test and the fed test each enrolled 30 healthy subjects given single oral dose 20 mg / 5 mg of the test and reference azilsartan amlodipine tablets. Plasma azilsartan and amlodipine concentrations at different time points were determined by LC-MS/MS. The pharmacokinetic parameters were calculated with the Phoenix WinNonlin software(version 7.0) based on non-compartmental analysis. SAS 9.4 software were used for bioequivalence evaluation. Results The pharmacokinetic parameters for test and reference preparations in fasting condition were as follows : azilsartan Cmax were (2306.67 ± 630.91) and (2364.00 ± 439.54) ng·mL-1, AUC0-t were (17390.72 ± 4664.15) and (16739.84 ± 3640.58) h·ng·mL-1, AUC0-∞ were (17569.85 ± 4678.80) and (17109.88 ± 3739.18) h·ng·mL-1, respectively. Amlodipine Cmax were (3.59 ± 1.12) and (3.39 ± 0.89) ng·mL-1, AUC0-t were (164.89 ± 67.54) and (153.04 ± 50.05) h·ng·mL-1, AUC0-∞ were (190.27 ± 88.10) and (182.39 ± 62.40) h·ng·mL-1, respectively. The pharmacokinetic parameters for test and reference preparations in fed condition were as follows : azilsartan Cmax were (2080.67 ± 451.72) and (2053.79 ± 424.14) ng·mL-1, AUC0-t were (17081.63 ± 4409.54) and (16273.82 ± 3816.66) h·ng·mL-1, AUC0-∞ were (17252.11 ± 4413.48) and (16440.06 ± 3828.30) h·ng·mL-1, respectively. Amlodipine Cmax were (3.30 ± 0.62) and (3.47 ± 0.72) ng·mL-1, AUC0-t were (149.50 ± 37.24) and (147.90 ± 35.28) h·ng·mL-1, AUC0-∞ were (174.22 ± 53.46) and (172.04 ± 49.55) h·ng·mL-1, respectively. The 90% confidence intervals of the geometric mean ratios of Cmax, AUC0-t, AUC0-∞ for the test preparation and the reference preparation were all between 80.00% and 125.00%. Conclusion The two azilsartan amlodipine tablets are bioequivalent in healthy subjects under fasting and fed conditions．