非那雄胺片在中国健康男性受试者空腹和餐后给药的人体生物等效性研究
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摘要
目的:研究非那雄胺片在中国健康男性人体内的药动学特征,并评价2种非那雄胺片的生物等效性。方法:24例健康男性受试者先后在空腹和餐后状态下随机交叉单剂量口服非那雄胺片受试制剂5 mg与参比制剂5 mg,采用超高效液相色谱串联质谱法(ultra high performance liquid chromatography-mass spectrometry,UPLC-MS/MS)测定不同时点血浆中非那雄胺的浓度,使用WinNonlin 7.0软件进行药动学参数计算,使用SAS 9.4软件进行生物等效性评价。结果:受试者空腹口服试验制剂与参比制剂后,血浆中非那雄胺分别在1.52(0.75～3)和1.75(0.75～4)h达到峰浓度(51.44±12.87)和(47.91±13.70)ng·mL~(-1);AUC_(0-t)分别为(342.58±98.34)和(337.73±87.89)h·ng·mL~(-1);AUC_(0-∞)分别为(348.98±99.92)和(346.65±91.87)h·ng·mL~(-1);t_(1/2)分别为(5.03±1.14)和(5.26±1.00)h。受试者餐后口服试验制剂与参比制剂后,血浆中非那雄胺分别在2.00(1～5)和2.00(0.75～4)h达到峰浓度(54.16±10.54)和(53.12±13.89)ng·mL~(-1);AUC_(0-t)分别为(363.44±95.83)和(360.30±98.48)h·ng·mL~(-1);AUC_(0-∞)分别为(372.37±96.62)和(367.89±98.34)h·ng·mL~(-1);t_(1/2)分别为(5.30±1.32)和(5.25±1.19)h。2种给药条件下,非那雄胺C_(max),AUC_(0-t)和AUC_(0-∞)的几何均值比率(受试制剂/参比制剂)的90%置信区间均在80.00%～125.00%范围内。结论:非那雄胺片受试制剂与参比制剂在空腹和餐后条件下均具有生物等效性。
Objective: To evaluate the pharmacokinetics and bioequivalence of two kinds finasteride tablets in Chinese healthy male volunteers. Methods: 24 healthy male volunteers were randomised to receive a single oral dose of 5 mg reference or test finasteride tablet under fasting and fed conditions,respectively. UPLC-MS/MS method was used to determine the concentrations of finasteride in plasma. Win Nolin 7. 0 and SAS 9. 4 software were used for PK parameters calculation and bioequivalence analysis,respectively. Results: The parameters of finasteride test and reference preparations under fasting condition were as follows: T_(max)were 1. 52(0. 75 ～ 3) h and 1. 75(0. 75 ～4) h; C_(max)were(51. 44 ± 12. 87) and(47. 91 ± 13. 70) ng·mL~(-1); AUC_(0-)twere(342. 58 ± 98. 34) and(337. 73 ±87. 89) h·ng·mL~(-1); AUC_(0-)∞were(348. 98 ± 99. 92) and(346. 65 ± 91. 87) h·ng·mL~(-1); t_(1/2) were(5. 03 ±1. 14) and(5. 26 ± 1. 00) h. And under fed condition: T_(max)were 2. 00(1 ～ 5) h and 2. 00(0. 75 ～ 4) h; C_(max)were (54. 16 ± 10. 54) and(53. 12 ± 13. 89) ng·mL~(-1); AUC_(0-)twere(363. 44 ± 95. 83) and(360. 30 ± 98. 48)h·ng·mL~(-1); AUC_(10-∞)were(372. 37 ± 96. 62) and(367. 89 ± 98. 34) h·ng·mL-; t_(1/2) were(5. 30 ± 1. 32) and(5. 25 ± 1. 19) h. The 90% confidence intervals for the rations of C_(max),AUC_(0-)tand AUC_(0-)∞were within the limits of 80. 00% ～ 125. 00% under those two conditions. Conclusion: Finasteride 5 mg test tablet preparations is bioequivalent to the 5 mg reference preparation under fasting and fed conditions.
Objective: To evaluate the pharmacokinetics and bioequivalence of two kinds finasteride tablets in Chinese healthy male volunteers. Methods: 24 healthy male volunteers were randomised to receive a single oral dose of 5 mg reference or test finasteride tablet under fasting and fed conditions,respectively. UPLC-MS/MS method was used to determine the concentrations of finasteride in plasma. Win Nolin 7. 0 and SAS 9. 4 software were used for PK parameters calculation and bioequivalence analysis,respectively. Results: The parameters of finasteride test and reference preparations under fasting condition were as follows: T_(max)were 1. 52(0. 75 ～ 3) h and 1. 75(0. 75 ～4) h; C_(max)were(51. 44 ± 12. 87) and(47. 91 ± 13. 70) ng·mL~(-1); AUC_(0-)twere(342. 58 ± 98. 34) and(337. 73 ±87. 89) h·ng·mL~(-1); AUC_(0-)∞were(348. 98 ± 99. 92) and(346. 65 ± 91. 87) h·ng·mL~(-1); t_(1/2) were(5. 03 ±1. 14) and(5. 26 ± 1. 00) h. And under fed condition: T_(max)were 2. 00(1 ～ 5) h and 2. 00(0. 75 ～ 4) h; C_(max)were (54. 16 ± 10. 54) and(53. 12 ± 13. 89) ng·mL~(-1); AUC_(0-)twere(363. 44 ± 95. 83) and(360. 30 ± 98. 48)h·ng·mL~(-1); AUC_(10-∞)were(372. 37 ± 96. 62) and(367. 89 ± 98. 34) h·ng·mL-; t_(1/2) were(5. 30 ± 1. 32) and(5. 25 ± 1. 19) h. The 90% confidence intervals for the rations of C_(max),AUC_(0-)tand AUC_(0-)∞were within the limits of 80. 00% ～ 125. 00% under those two conditions. Conclusion: Finasteride 5 mg test tablet preparations is bioequivalent to the 5 mg reference preparation under fasting and fed conditions.
引文
[1]WALSH PC.The effect of finasteride in men with benign prostatic hyperplasia[J].J Urol,1993,149(4):932-933.
[2]MCCONNELL JD,ROEHRBORN CG,BAUTISTA OM,et al.The long-term effect of doxazosin,finasteride,and combination therapy on the clinical progression of benign prostatic hyperplasia[J].N Engl J Med,2003,349(25):2387-2398.
[3]黄少情.非那雄胺治疗良性前列腺增生症的安全性及疗效评价[J].中国继续医学教育,2018,10(17):125-127.
[4]CLARK RV,HERMANN DJ,CUNNINGHAM GR,et al.Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride,a dual 5alpha-reductase inhibitor[J].J Clin Endocrinol Metab,2004,89(5):2179-2184.
[5]PRESTI JR,FAIR WR,ANDRIOLE G,et al.Multicenter,randomized,double-blind,placebo controlled study to investigate the effect of finasteride(MK-906)on stage D prostate cancer[J].J Urol,1992,148(4):1201-1204.
[6]国家药品监督管理局.以药动学参数为终点评价指标的化学药物仿制药人体生物等效性研究技术指导原则[S].2015.
[7]王鸿芡,罗柱,秦永平,等.UPLC-MS/MS法测定人血浆中非那雄胺浓度及2种片剂的生物等效性研究[J].中国新药杂志,2018,27(4):437-442.
[8]黄鑫,丁黎,沈建平,等.非那雄胺片在健康人体内的药动学及生物等效性研究[J].中国药科大学学报,2003,34(6):88-91.
[9]张国庆,柴逸峰,张银娣,等.非那雄胺2种片剂的药动学和相对生物利用度比较[J].中国新药与临床杂志,2004,23(10):684-686.
[10]彭文兴,朱荣华,刘晓磊,等.非那雄胺片的健康人体药动学研究[J].中国现代应用药学,2006,23(6):449-451.
[11]曾东向,任华益,李坤艳,等.非那雄胺胶囊的人体生物等效性研究[J].医药导报,2007,26(7):731-732.
[12]毕德忠,仇益群.自制非那雄胺片剂临床生物等效性评价[J].世界临床药物,2007,28(8):459-463,478.
[13]郝光涛,单婷婷,高洪志,等.非那雄胺颗粒在健康人体的生物等效性研究[J].中国药物应用与监测,2009,6(5):270-273.
[14]OHTAWA M,MORIKAWA H,SHIMAZAKI J.Pharmacokinetics and biochemical efficacy after single and multiple oral administration of N-(2-methyl-2-propyl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide,a new type of specific competitive inhibitor of testosterone 5α-reductase,in volunteers[J].Eur J Drug Metab Pharmacokinet,1991,16(1):15-21.
[15]SHIMAZAKI J,NOSE J.Phase I studies on MK-906,a 5α-reductase inhibitor:single dose(including food interaction)and multiple dose studies in healthy male volunteers[J].Yakuri To Chiryo,1990,18(17):2675-2694.
[16]MENEZES FG,RIBEIRO W,IFA DR,et al.Bioequivalence study of finasteride.Determination in human plasma by highpressure liquid chromatography coupled to tandem masss pectrometry[J].Arzneimittel Forschung,2001,51(2):145-150.
[17]ALMEIDA A,ALMEIDA S,FILIPE A,et al.Bioequivalence study of two different coated tablet formulations of finasteride in healthy volunteers[J].Arzneimittel Forschung,2005,55(4):218-222.
[18]CHEN L,JIANG X,HUANG L,et al.Bioequivalence of a single 10-mg dose of finasteride 5-mg oral disintegrating tablets and standard tablets in healthy adult male Han Chinese volunteers:a randomized sequence,open-label,two-way crossover study[J].Clin Ther,2009,31(10):2242-2248.
[2]MCCONNELL JD,ROEHRBORN CG,BAUTISTA OM,et al.The long-term effect of doxazosin,finasteride,and combination therapy on the clinical progression of benign prostatic hyperplasia[J].N Engl J Med,2003,349(25):2387-2398.
[3]黄少情.非那雄胺治疗良性前列腺增生症的安全性及疗效评价[J].中国继续医学教育,2018,10(17):125-127.
[4]CLARK RV,HERMANN DJ,CUNNINGHAM GR,et al.Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride,a dual 5alpha-reductase inhibitor[J].J Clin Endocrinol Metab,2004,89(5):2179-2184.
[5]PRESTI JR,FAIR WR,ANDRIOLE G,et al.Multicenter,randomized,double-blind,placebo controlled study to investigate the effect of finasteride(MK-906)on stage D prostate cancer[J].J Urol,1992,148(4):1201-1204.
[6]国家药品监督管理局.以药动学参数为终点评价指标的化学药物仿制药人体生物等效性研究技术指导原则[S].2015.
[7]王鸿芡,罗柱,秦永平,等.UPLC-MS/MS法测定人血浆中非那雄胺浓度及2种片剂的生物等效性研究[J].中国新药杂志,2018,27(4):437-442.
[8]黄鑫,丁黎,沈建平,等.非那雄胺片在健康人体内的药动学及生物等效性研究[J].中国药科大学学报,2003,34(6):88-91.
[9]张国庆,柴逸峰,张银娣,等.非那雄胺2种片剂的药动学和相对生物利用度比较[J].中国新药与临床杂志,2004,23(10):684-686.
[10]彭文兴,朱荣华,刘晓磊,等.非那雄胺片的健康人体药动学研究[J].中国现代应用药学,2006,23(6):449-451.
[11]曾东向,任华益,李坤艳,等.非那雄胺胶囊的人体生物等效性研究[J].医药导报,2007,26(7):731-732.
[12]毕德忠,仇益群.自制非那雄胺片剂临床生物等效性评价[J].世界临床药物,2007,28(8):459-463,478.
[13]郝光涛,单婷婷,高洪志,等.非那雄胺颗粒在健康人体的生物等效性研究[J].中国药物应用与监测,2009,6(5):270-273.
[14]OHTAWA M,MORIKAWA H,SHIMAZAKI J.Pharmacokinetics and biochemical efficacy after single and multiple oral administration of N-(2-methyl-2-propyl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide,a new type of specific competitive inhibitor of testosterone 5α-reductase,in volunteers[J].Eur J Drug Metab Pharmacokinet,1991,16(1):15-21.
[15]SHIMAZAKI J,NOSE J.Phase I studies on MK-906,a 5α-reductase inhibitor:single dose(including food interaction)and multiple dose studies in healthy male volunteers[J].Yakuri To Chiryo,1990,18(17):2675-2694.
[16]MENEZES FG,RIBEIRO W,IFA DR,et al.Bioequivalence study of finasteride.Determination in human plasma by highpressure liquid chromatography coupled to tandem masss pectrometry[J].Arzneimittel Forschung,2001,51(2):145-150.
[17]ALMEIDA A,ALMEIDA S,FILIPE A,et al.Bioequivalence study of two different coated tablet formulations of finasteride in healthy volunteers[J].Arzneimittel Forschung,2005,55(4):218-222.
[18]CHEN L,JIANG X,HUANG L,et al.Bioequivalence of a single 10-mg dose of finasteride 5-mg oral disintegrating tablets and standard tablets in healthy adult male Han Chinese volunteers:a randomized sequence,open-label,two-way crossover study[J].Clin Ther,2009,31(10):2242-2248.