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

doi:10.5246/jcps.2013.02.027

Abstract

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

CLC Number:

R945.1

Supporting:

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.

References

[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.