Drug-drug interaction study between a novel oral ibandronate formulation and metformin

Abstract

The novel excipient, sodium N-[8-(2-hy-droxybenzoyl)amino]caprylate (SNAC, CAS 203787-91-1) increases the oral bioavailability of co-formulated ibandronate (IBN, CAS 138926-19). The aim of this study was to investigate the effect of the IBN/SNAC formulation on the steady-state pharmacokinetics of metformin (CAS 657-24-9) and to assess safety and tolerability of IBN/SNAC when dosed in combination with metformin. Twenty-two healthy subjects received metformin on Days 1 to 6. On Day 7, subjects received metformin together with the IBN/ SNAC formulation. The safety and tolerability of IBN/SNAC co-administered with metformin was consistent with the known safety profile of the single medications. The increase in mean maximum plasma concentration (C_max) and mean overall exposure to metformin (AUC_0–τ) was approximately 7%. The entire 90% confidence intervals for the AUC- and C_max-ratios did fall within the acceptance region for bioequivalence (0.8-1.25). In summary, administration of the IBN/ SNAC formulation together with metformin did not lead to a significant increase in exposure to metformin. The study medication was well tolerated in healthy volunteers.

Key words

Drug-drug interaction - Ibandronate - Metformin - SNAC

• References

• 1 Chesnut III CH, Skag A, Christiansen C, Recker R, Stakke-stad JA, Hoiseth A et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004; 19: 1241-9
• 2 Miller PD, McClung MR, Macovei L, Stakkestad JA, Luckey M, Bonvoisin B et al. Monthly oral ibandronate therapy in postmenopausal osteoporosis: 1-year results from the MOBILE study. J Bone Miner Res. 2005; Aug; 20 (8) 1315-22
• 3 Reginster JY, Adami S, Lakatos P, Greenwald M, Stepan JJ, Silverman SL et al. Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2-year results from the MOBILE study. Ann Rheum Dis. 2006; May; 65 (5) 654-61
• 4 Barrett J, Worth E, Bauss F, Epstein S. Ibandronate: A clinical pharmacological and pharmacokinetic update. J Clin Pharmacol. 2004; Sep; 44 (9) 951-65
• 5 Leone-Bay A, Paton DR, Variano B, Leipold H, Rivera T, Miura-Fraboni J et al. Acylated non-alpha-amino acids as novel agents for the oral delivery of heparin sodium, USP. J Control Release. 1998; 50: 41-9
• 6 Tucker GT, Casey C, Phillips PJ, Connor H, Ward JD, Woods HF. Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br J Clin Pharmacol. 1981; Aug; 12 (2) 235-46
• 7 Song NN, Zhang SY, Liu CX. Overview of factors affecting oral drug absorption. Asian J Drug Metab Pharmacokinet. 2004; Aug; 4 (3) 167-76
• 8 Lin JH. Bisphosphonates: a review of their pharmacokinetic properties. Bone. 1996; Feb; 18 (2) 75-85
• 9 Brayden D, Creed E, O’Connell A, Leipold H, Agarwal R, Leone-Bay A. Heparin absorption across the intestine: effects of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate in rat in situ intestinal instillations and in caco-2 monolayers. Pharm Res. 1997; 14: 1772-9
• 10 Malkov D, Wang HZ, Dinh S, Gomez-Orellana I. Pathway of oral absorption of heparin with sodium N-[8-(2-hydroxy-benzoyl)amino]caprylate. Pharm Res. 2002; 19: 1180-4
• 11 Malkov D, Angelo R, Wang HZ, Flanders E, Tang H, Gomez-Orellana I. Oral delivery of insulin with the eligen technology: mechanistic studies. Curr Drug Deliv. 2005; 2: 191-7
• 12 Wu SJ, Robinson JR. Transport of human growth hormone across caco-2 cells with novel delivery agents: Evidence for p-glycoprotein involvement. J Control Release. 1999; 62: 171-7
• 13 Wu SJ, Robinson JR. Transcellular and lipophilic complex-enhanced intestinal absorption of human growth hormone. Pharm Res. 1999; Aug; 16 (8) 1266-72
• 14 Leone-Bay A, Sato M, Paton D, Hunt AH, Sarubbi D, Caroz-za M et al. Oral delivery of biologically active parathyroid hormone. Pharm Res. 2001; March; 18 (7) 964-70
• 15 Ding X, Rath P, Angelo R, Stringfellow T, Flanders E, Dinh S et al. Oral absorption enhancement of cromolyn sodium through non-covalent complexation. Pharm Res. 2004; Dec; 21 (12) 2196-206
• 16 Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995; Mar; 12 (3) 413-20
• 17 Noel M. Kinetic study of normal and sustained release dosage forms of metformin in normal subjects. Res Clin Forums. 1979; l (4) 33-44
• 18 Scheen AJ. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 1996; May; 30 (5) 359-71
• 19 Proctor WR, Bourdet DL, Thakker DR. Mechanisms underlying saturable intestinal absorption of metformin. Drug Metab Dispos. 2008; 36: 1650-8