阿哌沙班片在健康人体中的药动学及生物等效性评价
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摘要
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.
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.
引文
[1]张先龙.新型口服抗凝药物阿哌沙班[J].中华关节外科杂志:电子版,2014,8(4):543-546.
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[3]田国祥,魏万林,张灵.后华法林时代口服抗凝新秀:达比加群、利伐沙班、阿哌沙班[J].中国循证心血管医学杂志,2011,3(5):403-406.
[4]陈钧,陆伟,高科攀,等.两种盐酸特拉唑嗪片剂人体生物等效性评价[J].中国药学杂志,2003,38(6):446-448.
[5]孙媛媛,赵云丽,段蒙蒙,等.高效液相色谱法测定阿哌沙班中的有关物质[J].沈阳药科大学学报,2017(1):37-42.
[6]张琰,杨蕾,刘梅,等.苯磺酸氨氯地平片在健康人体的药动学及生物等效性评价[J].医学争鸣,2006,27(2):172-175.
[7]赵春杰,董娥,李欢欣.替硝唑片的相对生物利用度及其生物等效性评价[J].沈阳药科大学学报,2003,20(4):241-244.
[8]陈伟力,李雪宁,徐红蓉,等.国产与进口二甲双胍片剂人体生物等效性[J].中国临床药学杂志,2003,12(1):19-21.
[9]钟大放.以加权最小二乘法建立生物分析标准曲线的若干问题[J].药物分析杂志,1996,3(5):343-346.
[10]武少馨,李丹.RP-HPLC法测定阿哌沙班片的含量及有关物质[J].中国药房,2015,26(6):828-831.
[2]王磊,钟静芬,时惠麟.口服Xa因子直接抑制剂阿哌沙班的临床研究进展[J].上海医药,2012,19(17):17-20.
[3]田国祥,魏万林,张灵.后华法林时代口服抗凝新秀:达比加群、利伐沙班、阿哌沙班[J].中国循证心血管医学杂志,2011,3(5):403-406.
[4]陈钧,陆伟,高科攀,等.两种盐酸特拉唑嗪片剂人体生物等效性评价[J].中国药学杂志,2003,38(6):446-448.
[5]孙媛媛,赵云丽,段蒙蒙,等.高效液相色谱法测定阿哌沙班中的有关物质[J].沈阳药科大学学报,2017(1):37-42.
[6]张琰,杨蕾,刘梅,等.苯磺酸氨氯地平片在健康人体的药动学及生物等效性评价[J].医学争鸣,2006,27(2):172-175.
[7]赵春杰,董娥,李欢欣.替硝唑片的相对生物利用度及其生物等效性评价[J].沈阳药科大学学报,2003,20(4):241-244.
[8]陈伟力,李雪宁,徐红蓉,等.国产与进口二甲双胍片剂人体生物等效性[J].中国临床药学杂志,2003,12(1):19-21.
[9]钟大放.以加权最小二乘法建立生物分析标准曲线的若干问题[J].药物分析杂志,1996,3(5):343-346.
[10]武少馨,李丹.RP-HPLC法测定阿哌沙班片的含量及有关物质[J].中国药房,2015,26(6):828-831.