来曲唑片在中国健康绝经期女性志愿者人体生物等效性及安全性研究

doi:10.5246/jcps.2013.02.027

来曲唑片在中国健康绝经期女性志愿者人体生物等效性及安全性研究

刘一, 张逸凡, 王茜, 杨巍, 陈笑艳, 荆珊, 赵立波, 张春燕, 魏丽恵, 李小平, 冯婉玉, 钟大放^*, 方翼^*

1. 北京大学人民医院药剂科, 北京 100044
2. 中国科学院上海药物研究所, 上海 201203
3. 北京大学人民医院妇产科, 北京 100044

收稿日期:2012-12-17 修回日期:2013-02-15 出版日期:2013-03-18 发布日期:2013-03-18
通讯作者: 钟大放*, 方翼*

Bioequivalence and safety study of letrozole tablet in healthy Chinese postmenopausal women volunteers

Yi Liu, Yifan Zhang, Qian Wang, Wei Yang, Xiaoyan Chen, Shan Jing, Libo Zhao, Chunyan Zhang, Lihui Wei, Xiaoping Li, Wanyu Feng, Dafang Zhong^*, Yi Fang^*

1. Department of Pharmacy, Peking University People's Hospital, Beijing 100044, China
2. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
3. Department of Gynecology and Obstetrics, Peking University People's Hospital, Beijing 100044, China

Received:2012-12-17 Revised:2013-02-15 Online:2013-03-18 Published:2013-03-18
Contact: Dafang Zhong*, Yi Fang*

摘要/Abstract

摘要：

来曲唑是一种口服芳香酶抑制剂, 用于治疗绝经期女性乳腺癌。一项单剂量、随机、开放、双向交叉研究比较了2种2.5 mg的来曲唑片剂在空腹状态下的中国健康绝经期女性志愿者的人体生物等效性和安全性。在给药前以及给药后0.25、0.50、0.75、1.00、1.25、1.50、2.00、2.50、3.00、3.50、4.00、6.00、8.00、12.00、24.00、48.00、72.00、96.00、144.00、192.00和240.00小时采集血样。采用LC-MS/MS法测定来曲唑的血浆浓度。安全性的评估包括监测不良事件、生命体征及临床生物学数据等。共入选了30位中国健康绝经期女性受试者, 由于1位受试者发生了严重不良事件, 生物等效性研究仅包括了29位受试者的数据。lnCmax, AUC0-t, AUC0-∞ 的90% CIs分别为99.55%-115.17%, 97.35%-103.50%, 97.29%-103.96%, 这些数值均满足生物等效的标准。1位受试者 (3.3%) 服用参比制剂发生了严重不良事件, 10位受试者 (33.3%) 发生了13例次的轻度不良事件 (4位受试者服用受试制剂发生4例次轻度不良事件, 6位受试者服用参比制剂发生9例次轻度不良事件)。来曲唑单剂量2.5 mg的受试制剂和参比制剂在中国健康绝经期女性受试者人体生物等效, 两种药物在中国健康绝经期女性受试者中耐受性良好。中国临床试验注册号: ChiCTR-TRC-11001457。

关键词: 来曲唑, 生物等效性, 安全性, LC-MS/MS, 中国绝经期妇女

Abstract:

Letrozole is an orally active aromatase inhibitor for the treatment of postmenopausal women with breast cancer. A single-dose, randomized, open-label, two-way crossover study was designed to compare the bioequivalence and safety of two formulations of letrozole (2.5 mg/tablet), including a newly developed generic formulation (test) and a branded formulation (reference) in a group of healthy Chinese postmenopausal women volunteers under fasting conditions. Blood samples were obtained before study drug administration and at 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 144.00, 192.00 and 240.00 h after drug administration. Letrozole levels in plasma were analyzed using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The safety profile was evaluated by adverse events (AEs) record, and assessed by physical examination, vital signs, spontaneous reporting, and clinical laboratory results. A total of 30 healthy Chinese postmenopausal women were enrolled in this study; however, only 29 subjects were included in bioequivalence assessments due to serious adverse events (SAEs) in 1 subject. The 90% CIs for the ln-transformed ratios of Cmax, AUC0-t, and AUC0-∞ were 99.55%-115.17%, 97.35%-103.50%, and 97.29%-103.96%, respectively. All values met the predetermined criteria for assuming bioequivalence. One subject (3.3%) experienced SAE who received the reference formulation and 10 subjects (33.3%) reported a total of 13 mild AEs (4 reported from 4 subjects who received the test formulation, and 9 reported from 6 subjects who received the reference formulation). In this single-dose (2.5 mg) study, we found that the test and reference formulations of letrozole tablet met the regulatory definition for assuming bioequivalence in healthy Chinese postmenopausal women. Both formulations were generally well tolerated in the population studied. Chinese Clinical Trials registration number: ChiCTR-TRC-11001457.

Key words: Letrozole, Bioequivalence, Safety, LC-MS/MS, Chinese postmenopausal women

中图分类号:

R945.1

Supporting:

^*Corresponding author. Tel.: 86-21-50800738; 86-10-66583834

刘一, 张逸凡, 王茜, 杨巍, 陈笑艳, 荆珊, 赵立波, 张春燕, 魏丽恵, 李小平, 冯婉玉, 钟大放^*, 方翼^*. 来曲唑片在中国健康绝经期女性志愿者人体生物等效性及安全性研究[J]. , DOI: 10.5246/jcps.2013.02.027.

Yi Liu, Yifan Zhang, Qian Wang, Wei Yang, Xiaoyan Chen, Shan Jing, Libo Zhao, Chunyan Zhang, Lihui Wei, Xiaoping Li, Wanyu Feng, Dafang Zhong^*, Yi Fang^*. Bioequivalence and safety study of letrozole tablet in healthy Chinese postmenopausal women volunteers[J]. , DOI: 10.5246/jcps.2013.02.027.

参考文献

[1] Buzdar, A.U.; Robertson, J.F.; Eiermann, W.; Nabholtz, J.M. Cancer. 2002, 95, 2006-2016.
[2] Simpson, D.; Curran, M.P.; Perry, C.M. Drugs. 2004, 64, 1213-1238.
[3] Bhatnagar, A.S. Breast Cancer Res. Treat. 2007, 105, S7-S17.
[4] Sioufi, A.; Gauducheau, N.; Pineau, V.; Marfil, F.; Jaouen, A.; Cardot, J.M.; Godbillon, J.; Czendlik, C.; Howald, H.; Pfisterand, Ch.; Vreeland, F. Biopharm. Drug Dispos. 1997, 18, 779-789.
[5] Sioufi, A.; Sandrenan, N.; Godbillon, J.; Trunet, P.; Czendlik, C.; Howald, H.; Pfister, C.; Ezzet, F. Biopharm. Drug Dispos. 1997, 18, 489-497.
[6] Filipe, A.; Almeida, S.; Spínola, A.C.; Trabelsi, F.; Ortuño, J. Arzneimittelforschung. 2008, 58, 419-422.
[7] Dyderski, S.; Grześkowiak, E.; Szałek, E.; Szkutnik, D.; Dubai, V.; Drobnik, L. Arzneimittelforschung. 2005, 55, 514-519.
[8] Zarghi, A.; Foroutan, S.M.; Shafaati, A.; Khoddam, A. Chromatographia. 2007, 66, 747-750.
[9] Zhao, Y.T.; Xu, S.X.; Wang, S.F.; Zhou, Y.B.; Tian, J.; Ran, L.L.; Zuo, Y.L.; Ding, J.S. Guide Chin. Med. 2010, 8, 28-29, 59.
[10] Li, L.; Yan, J.; Deng, X.L.; Li, H.; Jing, X.; Ouyang, D.S. Anti-tumor Pharmacy. 2011, 1, 64-68.
[11] Tong, W.H.; Wen, J.Y.; Bao, Y.R.; Li, P.F.; Ma, P.; Wang, Y.; Liu, L.H. Chin. J. Clin. Pharmacol. 2012, 28, 131-134.
[12] World Medical Association. WMA Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects (Accessed March 26, 2006).
http://www.wma.net/en/30publications/10policies/ b3/index.html
[13] European Medicines Agency (EMEA). Note for guidance on good clinical practice (Accessed March 26, 2006). ICH topic E 6 (R1). http://www.emea.europa.eu/pdfs/human/ich/ 013595en.pdf
[14] State Food and Drug Administration of China. Guideline for Good Clinical Principles [in Chinese] (Accessed June 9, 2010). http://www.sda.gov.cn/WS01/CL0053/24473.html
[15] Shumaker, R.C. Drug Metab. Rev. 1986, 17, 331-348.
[16] State Food and Drug Administration, Center for Drug Evaluation. Guideline for bioavailability and bioequivalence studies of generic drug products [in Chinese] (Accessed December 1, 2009).
http://www.cde.org.cn/zdyz.do?method= largePage&id=2066
[17] US Department of Health and Human Services, US Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM). Guidance for Industry: Bioanalytical method validation (Accessed June 9, 2010). http://www.fda.gov/downloads/Drugs/Guidance Compliance Regulatory Information/Guidances/UCM070 107.pdf
[18] US Department of Health and Human Services, Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER). Guidance for Industry: Bioavailability and bioequivalence studies for orally administered drug products- general considerations (Accessed November 8, 2008). http://www.fda.gov/downloads/Drugs/Guidance Compliance Regulatory Information /Guidances/ucm070124.pdf
[19] US Food and Drug Administration. In vivo bioequivalence guidance. Pharmacopeial Forum. 1993, 19, 6501-6508.
[20] Tanni, H.; Shitara, Y.; Horie, T. Eur. J. Clin. Pharmacol. 2011, 67, 1017-1025.
[21] Nakajima, M.; Kuroiwa, Y.; Yokoi, T. Drug Metab. Rev. 2002, 34, 865-877.
[22] Daigo, S.; Takahashi, Y.; Fujieda, M.; Ariyoshi, N.; Yamazaki, H.; Koizumi,W.; Tanabe, S.; Saigenji, K.; Nagayama, S.; Ikeda, K.; Nishioka, Y.; Kamataki, T. Pharmacogenetics. 2002, 12, 299-306.
[23] Xu, C.; Rao, Y.S.; Xu, B.; Hoffmann, E.; Jones, J.; Sellers, E.M.; Tyndale, R.F. Biochem. Biophys. Res. Commun. 2002, 290, 318-324.