Clinical Drug Investigation

, Volume 32, Issue 12, pp 799–804 | Cite as

Pharmacokinetics of a Fixed-Dose Combination of Mitiglinide and Metformin versus Concurrent Administration of Individual Formulations in Healthy Subjects

A Randomized, Open-Label, Two-Treatment, Two-Period, Two-Sequence, Single-Dose, Crossover Study
  • Jin Ah Jung
  • Jung-Ryul Kim
  • Suk-Ran Kim
  • Tae-Eun Kim
  • Soo-Youn Lee
  • Jae-Wook Ko
  • Wooseong Huh
Original Research Article

Abstract

Background

In the treatment of diabetes mellitus, combined drugs with different mechanisms of action can be effective when adequate glycaemic control is difficult with monotherapy. A fixed-dose combination (FDC) tablet of mitiglinide and metformin has been developed as a second-line treatment for type 2 diabetes.

Objectives

The objective of this study was to compare the pharmacokinetics and safety of a FDC and a free combination of mitiglinide and metformin in healthy male subjects.

Methods

A randomized, open-label, two-period, two-treatment, single-dose, crossover study was conducted in 24 healthy Korean male subjects. In one period, a FDC tablet of mitiglinide and metformin (10 mg/500 mg) was administered, and in the other period, corresponding doses of individual formulations were administered.

Results

Twenty-four subjects were enrolled and 19 subjects completed the study. The geometric mean ratios (90 % confidence interval) of the maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from time zero to the time of the last measurable concentration (AUClast) were 0.9694 (0.8120, 1.1573) and 0.8951 (0.8440, 0.9494) for mitiglinide, and 1.0235 (0.9373, 1.1057) and 1.0542 (0.9697, 1.1460) for metformin, which were within the bioequivalence range. Among the 23 subjects who received study drugs, 15 subjects experienced 34 adverse events (AEs). The most frequently reported AEs were feeling hot and compensatory sweating. There were no serious AEs and no significant differences in the incidence of AEs between the two treatments.

Conclusion

A FDC tablet of mitiglinide and metformin was generally well tolerated in healthy male subjects. Administration of a FDC tablet and concomitant administration of individual formulations did not show significantly different pharmacokinetic profiles.

Notes

Acknowledgments

This study was sponsored by JW Pharmaceutical, Seoul, Korea, and supported by a grant from the Korea Healthcare Technology R&D Project, Ministry of Health, Welfare and Family Affairs, Republic of Korea (A070001). The authors would like to thank Jeong-Soo Yang (Senior Research Engineer) for conducting the bio-assay in this study. The authors have indicated that they have no other conflicts of interest regarding the content of this article.

References

  1. 1.
    National Diabetes Information Clearinghouse. National Diabetes Statistics, 2011. http://www.diabetes.niddk.nih.gov/dm/pubs/statistics. Accessed 12 Mar 2012
  2. 2.
    Standards of medical care in diabetes–2012. Diabetes Care. 2012;35 Suppl 1:S11–63.Google Scholar
  3. 3.
    Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American diabetes association (ADA) and the European association for the study of diabetes (EASD). Diabetes Care. 2012;35(6):1364–79.PubMedCrossRefGoogle Scholar
  4. 4.
    Shomali M. Add-on therapies to metformin for type 2 diabetes. Expert Opin Pharmacother. 2011;12(1):47–62.PubMedCrossRefGoogle Scholar
  5. 5.
    Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA. 1999;281(21):2005–12.PubMedCrossRefGoogle Scholar
  6. 6.
    Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012;122(6):253–70.PubMedCrossRefGoogle Scholar
  7. 7.
    Black C, Donnelly P, McIntyre L, Royle PL, Shepherd JP, Thomas S. Meglitinide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007;2:CD004654.PubMedGoogle Scholar
  8. 8.
    Shigeto M, Katsura M, Matsuda M, Ohkuma S, Kaku K. Nateglinide and mitiglinide, but not sulfonylureas, induce insulin secretion through a mechanism mediated by calcium release from endoplasmic reticulum. J Pharmacol Exp Ther. 2007;322(1):1–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Malaisse WJ. Mitiglinide: a rapid- and short-acting non-sulfonylurea insulinotropic agent for the treatment of type 2 diabetic patients. Expert Opin Pharmacother. 2008;9(15):2691–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Kusama H, Shibata N. Mitiglinide (KAD-1229). Nippon Rinsho. 2002;60(Suppl 9):559–65.PubMedGoogle Scholar
  11. 11.
    Cho YM, Koo BK, Son HY, Lee KW, Son HS, Choi DS, et al. Effect of the combination of mitiglinide and metformin on glycemic control in patients with type 2 diabetes mellitus. J Diabetes Investig. 2010;1(4):143–8.Google Scholar
  12. 12.
    Benford M, Milligan G, Pike J, Anderson P, Piercy J, Fermer S. Fixed-dose combination antidiabetic therapy: real-world factors associated with prescribing choices and relationship with patient satisfaction and compliance. Adv Ther. 2012;29(1):26–40.PubMedCrossRefGoogle Scholar
  13. 13.
    Sakane N. Antidiabetic fixed-dose combination tablet for the management of type 2 diabetes. Nihon Rinsho. 2012;70(1):165–70.PubMedGoogle Scholar
  14. 14.
    Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med. 2007;120(8):713–9.PubMedCrossRefGoogle Scholar
  15. 15.
    The World Medical Association. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. http://www.wma.net/en/30publications/10policies/b3/index.html. Accessed 12 Mar 2012
  16. 16.
    International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Guideline for good clinical practice. http://www.ich.org/LOB/media/MEDIA482.pdf. Accessed 12 May 2012
  17. 17.
    Zhang Y, Ding L, Tian Y, Yang J, Yang L, Wen A. Liquid chromatography/electrospray ionization tandem mass spectrometry for the quantification of mitiglinide in human plasma: validation and its application to pharmacokinetic studies. Biomed Chromatogr. 2008;22(8):873–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Porta V, Schramm SG, Kano EK, Koono EE, Armando YP, Fukuda K, et al. HPLC-UV determination of metformin in human plasma for application in pharmacokinetics and bioequivalence studies. J Pharm Biomed Anal. 2008;46(1):143–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Zhang L, Tian Y, Zhang Z, Chen Y. Simultaneous determination of metformin and rosiglitazone in human plasma by liquid chromatography/tandem mass spectrometry with electrospray ionization: application to a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;854(1–2):91–8.PubMedGoogle Scholar
  20. 20.
    Cai S, Huo T, Feng W, Chen L, Qin F, Li F. Quantitative determination of mitiglinide in human plasma by ultra-performance liquid chromatography/electrospray ionization tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2008;868(1–2):83–7.PubMedGoogle Scholar
  21. 21.
    Food and Drug Administration. Guidance for Industry: Bioanalytical Method Validation. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070107.pdf. Accessed 16 May 2012.
  22. 22.
    Food and Drug Administration. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products—General Considerations. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070124.pdf. Accessed 16 May 2012.
  23. 23.
    Sambol NC, Chiang J, O’Conner M, Liu CY, Lin ET, Goodman AM, et al. Pharmacokinetics and pharmacodynamics of metformin in healthy subjects and patients with noninsulin-dependent diabetes mellitus. J Clin Pharmacol. 1996;36(11):1012–21.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2012

Authors and Affiliations

  • Jin Ah Jung
    • 1
  • Jung-Ryul Kim
    • 1
  • Suk-Ran Kim
    • 1
  • Tae-Eun Kim
    • 1
  • Soo-Youn Lee
    • 1
    • 2
  • Jae-Wook Ko
    • 1
    • 3
  • Wooseong Huh
    • 1
    • 4
  1. 1.Department of Clinical Pharmacology and Therapeutic, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulKorea
  2. 2.Department of Laboratory Medicine and Genetics, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulKorea
  3. 3.Samsung Advanced Institute for Health Sciences and TechnologySeoulKorea
  4. 4.Department of Internal Medicine, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulKorea

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