Bioequivalence and Pharmacokinetic Comparison of 3 Metformin Extended/Sustained Release Tablets in Healthy Indian Male Volunteers

Abstract

This study was undertaken to compare the bioavailability and pharmacokinetic properties of 3 marketed product of metformin (CAS 1115-70-4) extended/sustained release formulation in Indian male volunteers. Study was designed as an open-label, randomized, 3-treatment, single-dose, crossover, bioavailability study comparing 3 marketed brands of 500 mg metformin extended/sustained release tablets in 18 healthy human male volunteers under fed condition. A single oral dose of 500 mg metformin sustained release products, test A (Glycomet SR), test B (Bigomet SR) and extended release reference product was administered as per computer generated randomization schedule during 3 period of the study having 7 days of washout period. A liquid Chromatography mass spectroscopy method for the determination of metformin in human plasma was developed and validated using metformin-D6 as an internal standard. A noncompartment pharmacokinetic method was employed to determine the pharmacokinetic parameters (C_max, T_max, AUC_0–t, AUC_0–∞ and t½) of metformin using WinNonlin-Node 4.0 software. C_max, AUC_0–t and AUC_0–∞ were used to test for bioequivalence after log transformation of plasma data. The predetermined regulatory range of 90% CI for bioequivalence was 0.80 to 1.25. The 90% confidence intervals for log transformed data for C_max, AUC_0–t and AUC_0–∞ for test A vs. reference were 82.11–98.91, 86.29–102.17 and 86.34–102.59 respectively whereas for test B vs. reference were 104.39–125.76, 94.78–112.22 and 92.85–110.33 respectively. The results of this study suggest that the test A was bioequivalent to reference product, whereas test B was not as per regulatory defined criteria.

Key words

metformin - extended/sustained release - pharmacokinetics - bioequivalence

• References

• 1 Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med 2002; 137: 25-33
• 2 Goodarzi MO, Bryer-Ash M. Metformin revisited: re-evaluation of its properties and role in the pharmacopoeia of modern antidiabetic agents. Diabetes Obes Metab 2005; 7: 654-665
• 3 Bailey CJ. Treating insulin resistance in type 2 diabetes with metformin and thiazolidinediones. Diabetes Obes Metab 2005; 7: 675-691
• 4 Timmins P, Donahue S, Meeker J et al. Steady-state pharmacokinetics of a novel extended-release metformin formulation. Clin Pharmacokinet 2005; 44: 721-729
• 5 Prescribing Information Glucophage & Glucophage XR (metformin and metformin extended release tablets). USA Prinston (NJ): Bristol-Myers Squibb Company, January 2009
• 6 Schwartz SL, Gordi T, Hou E et al. Clinical development of metformin extended-release tablets for type 2 diabetes: an overview. Expert Opin Drug Metab Toxicol 2008; 4: 1235-1243
• 7 Al Hawari S, AlGaai E, Yusuf A et al. Bioequivalence study of two metformin formulations. Arzneimittelforschung 2007; 57: 192-195
• 8 Atanasova I, Bozhinova K, Todorova D et al. Pharmacokinetics and comparative bioavailability of two metformin formulations after single-dose administration in healthy subjects. Clin Drug Investig 2003; 23: 743-749
• 9 Najib N, Idkaidek N, Beshtawi M et al. Bioequivalence evaluation of two brands of metformin 500 mg tablets (Dialon & Glucophage) – in healthy human volunteers. Biopharm Drug Dispos 2002; 23: 301-306
• 10 Yuen KH, Wong JW, Billa N et al. Bioequivalence of a generic metformin tablet preparation. Int J Clin Pharmacol Ther 1999; 37: 319-322
• 11 Li J, Jin Y, Wang TY et al. Relative bioavailability and bioequivalence of metforphin hydrochloride extended-released and immediate-released tablets in healthy Chinese volunteers. Eur J Drug Metab Pharmacokinet 2007; 32: 21-28
• 12 US Food and Drug Administration, Guidance for Industry: [Internet] Bioanalytical Method Validation. May2001 (cited on November 13, 2008). Available from www.fda.gov/CDER/GUIDANCE/4252fnl.htm
• 13 US Food and Drug Administration Guidance for Industry:[Internet]. Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations, 2003(cited on November 13, 2008) Available from http://www.cdsco.nic.in/html/BE%20Guidelines%20Draft%20Ver10%20March%2016,%2005.pdf
• 14 Central Drugs Standard Control Organization Guidelines for bioavailability & bioequivalence studies. [Internet]. Ministry of Health and Family Affair, Govt. of India, March, 2005 (cited on November 2008). Available from http://www.cdsco.nic.in/html/BE%20Guidelines%20Draft%20Ver10%20March%2016,%2005.pdf
• 15 Shu Y, Sheardown SA, Brown C et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 2007; 117: 1422-1431
• 16 Song IS, Shin HJ, Shim EJ et al. Genetic Variants of the Organic Cation Transporter 2 Influence the Disposition of Metformin. Clin Pharmacol Ther 2008; 84: 559-562
• 17 Lalau JD, Lacroix C, Compagnon P et al. Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care 1995; 18: 779-784