阿哌沙班片在健康人体中的药动学及生物等效性评价

Pharmacokinetics and bioequivalence of apixaban tablets in healthy human

目的:研究阿哌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:26名健康受试者口服阿哌沙班受试试剂和参比试剂(艾乐妥),采用两周期、两交叉空腹/餐后状态自身对照的试验方法,用液相色谱-质谱联用法测定服药后72 h内16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Tmax,Cmax,t1/2和AUC0-72h分别为(2.67±1.14)h,(89.5±24.9)ng·m L-1,(7.15±2.77)h,(765.24±218.77)h·ng·m L-1和(2.10±0.75)h,(97.6±22.1)ng·m L-1,(6.14±2.06)h,(749.55±199.02)h·ng·m L-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Tmax,Cmax,t1/2和AUC0-72h分别为(2.46±1.23)h,(72.6±21.3)ng·m L-1,(9.61±5.23)h,(623.21±167.10)h·ng·m L-1和(2.71±0.93)h,(69.1±19.8)ng·m L-1,(9.02±3.03)h,(595.67±193.08)h·ng·m L-1。空腹和餐后状态下的相对生物利用度分别为102.09%和104.62%(以均值计算),表明2种制剂具有生物等效性。结论:本研究采用LC-MS/MS方法测定人血浆中阿哌沙班含量,该方法准确快速,灵敏度高,重现性好,为临床安全用药提供理论参考。

Objective： To study the pharmacokinetic parameters of apixaban tablets,and evaluate the bioequivalence of two medical preparations. Methods： An open,randomized and two-period crossover fasting/fed study with a five-days washout interval was performed in 26 healthy volunteers. Apixaban concentration in plasma samples collected at 16 time points in 72 h were analyzed by LC-MS/MS,and main pharmacokinetic parameters were calculated. Bioequivalence was evaluated by analysis of variance,two one-side t test and 90% confidence interval analysis. Results： The subjects were given test tablets and reference tablets orally under fasting condition parameter of tested and referenced tablets were Tmax,Cmax,t1/2,AUC0-72 hwere（ 2. 67 ± 1. 14） h,（ 89. 5 ± 24. 9）ng·m L-1,（ 7. 15 ± 2. 77） h,（ 765. 24 ± 218. 77） h·ng·m L-1 and（ 2. 10 ± 0. 75） h,（ 97. 6 ± 22. 1） ng·m L-1,（ 6. 14 ± 2. 06） h,（ 749. 55 ± 199. 02） h·ng·m L-1. The subjects were given test tablets and reference tablets afer eating the high fat diet,the main pharmacokinetics parameter of tested and referenced tablets were Tmax,Cmax,t1/2,AUC0-72 hwere（ 2. 46 ± 1. 23） h,（ 72. 6 ± 21. 3） ng·m L-1,（ 9. 61 ± 5. 23） h,（ 623. 21 ± 167. 10） h·ng·m L-1 and（ 2. 71 ± 0. 93） h,（ 69. 1 ± 19. 8） ng·m L-1,（ 9. 02 ± 3. 03） h,（ 595. 67 ± 193. 08） h·ng·m L-1. The fasting test relative bioavailability of apixaban was 102. 09%,and the fed test relative bioavailability of apixaban was104. 62%. Conclusion： The LC-MS/MS method established for determination of apixaban in human plasma was accurate and rapid,with high sensitivity and good reproducibility,providing references for clinical safety medication.