马来酸依那普利片在中国健康受试者的药代动力学和生物等效性研究
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摘要
目的研究马来酸依那普利片在中国健康受试者空腹及餐后条件下单剂量给药时药代动力学和人体生物等效性。方法采用单中心、单剂量、随机、开放、两周期交叉的设计。受试者每周期空腹或者餐后给予相应顺序的受试药物或参比药物10 mg。用液相色谱串联质谱法(LC-MS/MS)测定血浆中依那普利和依那普利拉的浓度。使用Phoenix Win Nonlin软件(Pharsight Corporation,7. 0)按非房室模型对血浆中的依那普利和依那普利拉的药代动力学参数进行计算,使用SAS9. 4软件分析生物等效性。结果空腹口服受试药物和参比药物的依那普利的达峰浓度C_(max)分别为(91. 27±23. 80)和(82. 39±22. 93) ng·m L~(-1);AUC_(0-t)分别为(148. 44±37. 20)和(139. 82±30. 66) ng·h·m L~(-1); AUC_(0-∞)分别为(150. 29±37. 07)和(141. 81±31. 19) ng·h·m L~(-1);达峰时间T_(max)中位数(最小值,最大值)分别为0. 75(0. 50,1. 33)和0. 75(0. 50,1. 67) h。餐后口服受试药物和参比药物的依那普利的达峰浓度C_(max)分别为(55. 04±13. 63)和(54. 48±11. 63) ng·m L~(-1); AUC0-t分别为(106. 94±18. 67)和(109. 45±20. 70)ng·h·m L~(-1); AUC_(0-∞)分别为(108. 47±18. 81)和(111. 28±20. 85)ng·h·m L~(-1);达峰时间T_(max)中位数(最小值,最大值)分别为1. 33(0. 75,3. 50)和1. 33(0. 75,3. 50) h。空腹和餐后口服受试药物与参比药物的C_(max),AUC_(0-t),AUC_(0-∞)的几何均值比的90%置信区间均在生物等效性范围80. 00%～125. 00%。结论受试药物和参比药物在空腹或餐后口服时具有生物等效性。
Objective To study the pharmacokinetics and bioequivalence of enalapril maleate tablets in Chinese healthy volunteers under fasting and postprandial conditions. Methods A single dose test and reference formulations 10 mg were taken orally under fasting and postprandial conditions according to an open randomized two way crossover design in a single center. The concentration of enalapril and enalaprilat were determined by Liquid Chromatography-Tandem Mass Spectrometry. The pharmacokinetic parameters were calculated by Phoenix Win Nonlin software( Pharsight Corporation,7. 0) according to the non-compartment model,and bioequivalence was analyzed by SAS 9. 4 software. Results The main pharmacokinetic parameters of test and reference formulation under fasting and postprandial conditions were as follow.The results for enalapril under fasting conditions: C_(max) were( 91. 27 ± 23. 80) and( 82. 39 ± 22. 93) ng · m L~(-1);AUC_(0-t) were( 148. 44 ± 37. 20) and( 139. 82 ± 30. 66) ng · h · m L~(-1); AUC_(0-∞) were( 150. 29 ± 37. 07) and( 141. 81 ± 31. 19) ng·h·m L~(-1); T_(max) [median( minimum,maximum) ]were 0. 75( 0. 50,1. 33) and 0. 75( 0. 50,1. 67) h. The results for enalapril under postprandial conditions : C_(max) were( 55. 04 ± 13. 63) and( 54. 48 ± 11. 63)ng·m L~(-1); AUC_(0-t) were( 106. 94 ± 18. 67) and( 109. 45 ± 20. 70) ng·h·m L~(-1); AUC_(0-∞) were( 108. 47 ± 18. 81)and( 111. 28 ± 20. 85) ng · h · m L~(-1); T_(max) [median( minimum,maximum) ] were 1. 33( 0. 75,3. 50) and 1. 33( 0. 75,3. 50) h. The 90% confidence interval of the geometric mean ratio of C_(max),AUC_(0-t) and AUC_(0-∞) of the test and reference under fasting and postprandial conditions were within the bioequivalence range of 80. 00% to 125. 00%.Conclusion The two preparations of enalapril maleate tablets were bioequivalent under fasting and postprandial conditions.
Objective To study the pharmacokinetics and bioequivalence of enalapril maleate tablets in Chinese healthy volunteers under fasting and postprandial conditions. Methods A single dose test and reference formulations 10 mg were taken orally under fasting and postprandial conditions according to an open randomized two way crossover design in a single center. The concentration of enalapril and enalaprilat were determined by Liquid Chromatography-Tandem Mass Spectrometry. The pharmacokinetic parameters were calculated by Phoenix Win Nonlin software( Pharsight Corporation,7. 0) according to the non-compartment model,and bioequivalence was analyzed by SAS 9. 4 software. Results The main pharmacokinetic parameters of test and reference formulation under fasting and postprandial conditions were as follow.The results for enalapril under fasting conditions: C_(max) were( 91. 27 ± 23. 80) and( 82. 39 ± 22. 93) ng · m L~(-1);AUC_(0-t) were( 148. 44 ± 37. 20) and( 139. 82 ± 30. 66) ng · h · m L~(-1); AUC_(0-∞) were( 150. 29 ± 37. 07) and( 141. 81 ± 31. 19) ng·h·m L~(-1); T_(max) [median( minimum,maximum) ]were 0. 75( 0. 50,1. 33) and 0. 75( 0. 50,1. 67) h. The results for enalapril under postprandial conditions : C_(max) were( 55. 04 ± 13. 63) and( 54. 48 ± 11. 63)ng·m L~(-1); AUC_(0-t) were( 106. 94 ± 18. 67) and( 109. 45 ± 20. 70) ng·h·m L~(-1); AUC_(0-∞) were( 108. 47 ± 18. 81)and( 111. 28 ± 20. 85) ng · h · m L~(-1); T_(max) [median( minimum,maximum) ] were 1. 33( 0. 75,3. 50) and 1. 33( 0. 75,3. 50) h. The 90% confidence interval of the geometric mean ratio of C_(max),AUC_(0-t) and AUC_(0-∞) of the test and reference under fasting and postprandial conditions were within the bioequivalence range of 80. 00% to 125. 00%.Conclusion The two preparations of enalapril maleate tablets were bioequivalent under fasting and postprandial conditions.
引文
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[2]HALDER D,DAN S,PAL M M,et al.LC-MS/MS assay for quantitation of enalapril and enalaprilat in plasma for bioequivalence study in Indian subjects[J].Future Sci OA,2017,3(1):165.
[3]ALEMAYEHU C,MITCHELL G,ASEFFA A,et al.A series of N-of-1 trials to assess the therapeutic interchangeability of two enalapril formulations in the treatment of hypertension in Addis Ababa,Ethiopia:study protocol for a randomized controlled trial[J].Trials,2017,18(1):470.
[4]LOPES R A,NEVES FDE A.Meta-analysis for bioequivalence studies:interchangeability of generic drugs and similar containing Hydrochlorothiazide is possible but not with Enalapril Maleate[J].JBras Nefrol,2010,32(2):173-181.
[5]MOFFETT B S,DISANTO A R,ESPINOSA O,et al.Bioequivalence of enalapril oral solution for treatment of pediatric hypertension and enalapril tablets[J].Clin Pharmacol Drug Dev,2014,3(6):393-398.