Bioequivalence of Saxagliptin/Metformin Extended-Release (XR) Fixed-Dose Combination Tablets and Single-Component Saxagliptin and Metformin XR Tablets in Healthy Adult Chinese Subjects
- 306 Downloads
Background and Objectives
As compared with individual tablets, saxagliptin/metformin extended-release (XR) fixed-dose combination (FDC) tablets offer the potential for increased patient compliance with the convenience of once daily dosing. The aim of the present study was to show that the FDC of saxagliptin and metformin XR is bioequivalent to co-administration of the individual components when given to Chinese subjects residing in China.
This was a randomized, open-label, single-dose, two-period, cross-over pharmacokinetic study in two cohorts of healthy adult Chinese male subjects (n = 32 in each cohort) under fed conditions. In cohort 1, the pharmacokinetic properties of a saxagliptin/metformin XR 5/500 mg FDC tablet were compared with those of co-administration of a 5 mg saxagliptin tablet and a 500 mg metformin XR tablet. In cohort 2, the pharmacokinetic properties of a saxagliptin/metformin XR 5/1,000 mg FDC tablet were compared with those of co-administration of a 5 mg saxagliptin tablet and 2 × 500 mg metformin XR tablets. The two cohorts were independent of each other with respect to treatment and results. The pharmacokinetic properties of the active metabolite of saxagliptin (5-hydroxy-saxagliptin), as well as the safety and tolerability of each treatment, were also evaluated.
For both cohorts, saxagliptin and metformin in the FDCs were bioequivalent to the individual components, as the limits of the 90 % confidence intervals of the geometric least squares mean ratios were contained within the 80–125 % bioequivalence limits for the area under the plasma concentration–time curve parameters and within the 70–143 % bioequivalence limits for the maximum plasma concentration. Similar exposures of 5-hydroxy-saxagliptin were observed with the two treatment regimens within each cohort. Co-administration of saxagliptin and metformin XR was generally safe and well tolerated as the FDCs or as individual tablets.
Saxagliptin/metformin XR 5/500 mg and saxagliptin/metformin XR 5/1,000 mg FDCs were bioequivalent to individual tablets of saxagliptin and metformin XR of the same strengths and were generally well tolerated. These results in healthy Chinese subjects are consistent with those of previous assessments of saxagliptin/metformin XR FDC in the saxagliptin clinical development programme.
KeywordsMetformin Saxagliptin Acute Tonsillitis Metformin Hydrochloride Healthy Chinese Subject
The authors wish to thank the staff and subjects of the Phase I Unit at Peking University Third Hospital in Beijing, China, for their contributions to these studies. The design, funding and publication support for this study was provided by AstraZeneca and the Bristol-Myers Squibb Company. All authors contributed to the conduct of the study and the data analysis/interpretation, and independently drafted, critically revised and approved the final manuscript. Haiyan Li is a current employee of Peking University Third Hospital. Anders Gummesson, Michael Gillen, John Xu, Mohammad Niazi and Boaz Hirshberg were employees of AstraZeneca at the time of this research. Editorial assistance was provided by Kevin Schofield and Janet E. Matsuura of Complete Healthcare Communications, Inc. (Chadds Ford, PA, USA) and was funded by AstraZeneca and the Bristol-Myers Squibb Company.
This study was performed in accordance with the Declaration of Helsinki and in compliance with the International Conference on Harmonisation/Good Clinical Practice and applicable regulatory requirements. The final clinical study protocol, including the information and consent forms, was approved by the Peking University Third Hospital Medical Science Research Ethics Committee before any subjects were enrolled. All subjects provided written informed consent prior to initiation of the study.
- 7.Boulton DW, Geraldes M. Safety, tolerability, pharmacokinetics and pharmacodynamics of once-daily oral doses of saxagliptin for 2 weeks in type 2 diabetic and healthy subjects. Diabetes. 2007;56(Suppl 1):606P.Google Scholar
- 10.Chacra AR, Tan GH, Apanovitch A, Ravichandran S, List J, Chen R. Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial. Int J Clin Pract. 2009;63(9):1395–406.PubMedCrossRefPubMedCentralGoogle Scholar
- 11.DeFronzo RA, Hissa MN, Garber AJ, Luiz Gross J, Yuyan Duan R, Ravichandran S, et al. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care. 2009;32(9):1649–55.PubMedCrossRefPubMedCentralGoogle Scholar
- 13.Jadzinsky M, Pfutzner A, Paz-Pacheco E, Xu Z, Allen E, Chen R. Saxagliptin given in combination with metformin as initial therapy improves glycaemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Diabetes Obes Metab. 2009;11(6):611–22.PubMedCrossRefGoogle Scholar
- 19.Scheen AJ, Charpentier G, Ostgren CJ, Hellqvist A, Gause-Nilsson I. Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes Metab Res Rev. 2010;26(7):540–9.PubMedCrossRefGoogle Scholar
- 21.Stenlof K, Raz I, Neutel J, Ravichandran S, Berglind N, Chen R. Saxagliptin and metformin XR combination therapy provides glycemic control over 24 hours in patients with T2DM inadequately controlled with metformin. Curr Med Res Opin. 2010;26(10):2355–63. doi: 10.1185/03007995.2010.511090.PubMedCrossRefGoogle Scholar
- 23.American Diabetes Association. Standards of medical care in diabetes-2012. Diabetes Care. 2012;35(Suppl 1):S11–63.Google Scholar
- 24.Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193–203.PubMedCrossRefPubMedCentralGoogle Scholar
- 27.Glucophage® and Glucophage® XR metformin HCl tablets and metformin HCl extended-release tablets. Princeton: Bristol-Myers Squibb Company; 2009.Google Scholar
- 29.Patel C, Komoroski B, Brenner E, et al. No meaningful pharmacokinetic drug–drug interactions between saxagliptin and metformin in healthy subjects. Denver: American College of Clinical Pharmacy Annual Meeting; 2007.Google Scholar
- 30.Boulton DW, Smith CH, Li L, Huang J, Tang A, LaCreta FP. Bioequivalence of saxagliptin/metformin extended-release (XR) fixed-dose combination tablets and single-component saxagliptin and metformin XR tablets in healthy adult subjects. Clin Drug Investig. 2011;31(9):619–30.PubMedCrossRefGoogle Scholar
- 31.People’s Republic of China State Food and Drug Administration. Technique guideline for human bioavailability and bioequivalence studies on chemical drug products [in Chinese]. 2005. http://www.cde.org.cn/zdyz.do?method=largePage&id=2066. Accessed 27 Feb 2014.