Effect of Semaglutide on the Pharmacokinetics of Metformin, Warfarin, Atorvastatin and Digoxin in Healthy Subjects

Helene Hausner, Julie Derving Karsbøl, Anders G Holst, Jacob B Jacobsen, Frank-Dietrich Wagner, Georg Golor, Thomas W Anderson, Helene Hausner, Julie Derving Karsbøl, Anders G Holst, Jacob B Jacobsen, Frank-Dietrich Wagner, Georg Golor, Thomas W Anderson

Abstract

Background and objective: Semaglutide is a glucagon-like peptide-1 analogue in development for the once-weekly treatment of type 2 diabetes mellitus. Its effect on the rate and extent of absorption of concomitant oral medications (metformin, warfarin, atorvastatin and digoxin) was evaluated in healthy subjects.

Methods: Subjects received metformin (500 mg twice daily for 3.5 days), warfarin (25 mg, single dose), atorvastatin (40 mg, single dose) or digoxin (0.5 mg, single dose) before and with subcutaneous semaglutide treatment at steady state (1.0 mg). Lack of drug-drug interaction was concluded if the 90% confidence intervals for the area under the plasma concentration-time curve ratio before and with semaglutide were within a pre-specified interval (0.80-1.25).

Results: Overall, metformin, warfarin, atorvastatin and digoxin pharmacokinetics were not affected to a clinically relevant degree with semaglutide co-administration. Estimated area under the plasma concentration-time curve ratios for all concomitant medications before and with semaglutide treatment were within the pre-specified interval. In addition, semaglutide did not affect maximum plasma concentration of concomitant medications to a relevant degree. Furthermore, no clinically relevant change in international normalised ratio response to warfarin was observed with semaglutide co-administration. Most adverse events with semaglutide treatment were mild or moderate. Adverse events with semaglutide and co-administered medication were comparable to those reported during treatment with semaglutide alone, and were mostly gastrointestinal related.

Conclusions: No clinically significant pharmacokinetic or pharmacodynamic interactions were identified and no new safety issues observed with combined treatment with semaglutide. This suggests that no dose adjustments should be required when semaglutide is administered concomitantly with these medications.

Conflict of interest statement

Conflict of interest

FW and GG have no conflicts of interest to declare. HH, DK, AH, JJ and TA are full-time employees of Novo Nordisk.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Funding

This study was funded by Novo Nordisk. AXON Communications provided editorial and medical writing assistance, which was funded by Novo Nordisk.

Informed consent

Informed consent was obtained from all individual participants included in the study. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.

Figures

Fig. 1
Fig. 1
Study design. Atorv atorvastatin, Dig digoxin, Met metformin, Ortho-OH ortho-hydroxylated atorvastatin metabolite, Para-OH para-hydroxylated atorvastatin metabolite, SS steady state, War warfarin. Asterisk Metformin was administered 3.5 days prior to the metformin pharmacokinetic sampling visit. Dagger Administered 48 h after the fifth dose of semaglutide 1.0 mg. Double dagger Administered 48 h after the sixth dose of semaglutide 1.0 mg. Section sign In Study 2, follow-up visit was at visit 12. The subjects received metformin and warfarin in Study 1, and atorvastatin and digoxin in Study 2
Fig. 2
Fig. 2
Mean pharmacokinetic profiles of metformin (a), S-warfarin* (b), atorvastatin (c) and digoxin (d) before and with semaglutide treatment. Reference line for the lower limit of quantification. Values below the lower limit of quantification are imputed. Asterisk R-warfarin curves are not included here but followed a similar pattern to the S-warfarin curves
Fig. 3
Fig. 3
Estimated exposure ratios for metformin, warfarin, atorvastatin and digoxin before and with semaglutide treatment. Estimated ratios, before vs. with semaglutide treatment and 90% confidence intervals are shown. AUC area under the plasma concentration–time curve, Cmax maximum plasma concentration (Cmax limits for atorvastatin and digoxin were not predefined)
Fig. 4
Fig. 4
Mean international normalised ratio (INR) profile for warfarin

References

    1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140–149. doi: 10.2337/dc14-2441.
    1. Fox CS, Golden SH, Anderson C, et al. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care. 2015;38(9):1777–1803. doi: 10.2337/dci15-0012.
    1. Bailey CJ, Blonde L, Del Prato S, et al. Global Partnership for Effective Diabetes Management. What are the practical implications for treating diabetes in light of recent evidence? Updated recommendations from the Global Partnership for Effective Diabetes Management. Diab Vasc Dis Res. 2009;6(4):283–287. doi: 10.1177/1479164109341691.
    1. Warfarin. Summary of product characteristics. (2017). Accessed 6 Feb 2017.
    1. Digoxin. Summary of product characteristics. (2017). Accessed 6 Feb 2017.
    1. Atorvastatin. Summary of product characteristics. (2017). Accessed 6 Feb 2017.
    1. Ibrahim IA, Kang E, Dansky KH. Polypharmacy and possible drug-drug interactions among diabetic patients receiving home health care services. Home Health Care Serv Q. 2005;24(1–2):87–99. doi: 10.1300/J027v24n01_07.
    1. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–322. doi: 10.1056/NEJMoa1603827.
    1. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–1844. doi: 10.1056/NEJMoa1607141.
    1. Lau J, Bloch P, Schaffer L, et al. Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J Med Chem. 2015;58(18):7370–7380. doi: 10.1021/acs.jmedchem.5b00726.
    1. Roffel AF, Jensen L, van Lier JJ, et al. Absorption, metabolism and excretion of 3H-semaglutide following a single, subcutaneous dose in healthy male subjects. Diabetologia. 2015;58(suppl 1):S1–S607.
    1. Kapitza C, Nosek L, Jensen L, et al. Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel. J Clin Pharmacol. 2015;55(5):497–504. doi: 10.1002/jcph.443.
    1. Hjerpsted J, Axelsen MB, Brooks A, et al. Semaglutide improves postprandial glucose and lipid metabolism and delays first-hour gastric emptying in subjects with obesity. In: American Diabetes Association 76th Scientific Sessions. New Orleans, LA; 2016 (#763).
    1. Thomsen RW, Baggesen LM, Sogaard M, et al. Early glycaemic control in metformin users receiving their first add-on therapy: a population-based study of 4,734 people with type 2 diabetes. Diabetologia. 2015;58(10):2247–2253. doi: 10.1007/s00125-015-3698-1.
    1. Bush M, Scott R, Watanalumlerd P, et al. Effects of multiple doses of albiglutide on the pharmacokinetics, pharmacodynamics, and safety of digoxin, warfarin, or a low-dose oral contraceptive. Postgrad Med. 2012;124(6):55–72. doi: 10.3810/pgm.2012.11.2613.
    1. Hurren KM, Pinelli NR. Drug-drug interactions with glucagon-like peptide-1 receptor agonists. Ann Pharmacother. 2012;46(5):710–717. doi: 10.1345/aph.1Q583.
    1. Amidon GL, Lennernas 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;12(3):413–420. doi: 10.1023/A:1016212804288.
    1. McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia. 2016;59(3):426–435. doi: 10.1007/s00125-015-3844-9.
    1. Marathe PH, Wen Y, Norton J, et al. Effect of altered gastric emptying and gastrointestinal motility on metformin absorption. Br J Clin Pharmacol. 2000;50(4):325–332. doi: 10.1046/j.1365-2125.2000.00264.x.
    1. Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011;50(2):81–98. doi: 10.2165/11534750-000000000-00000.
    1. Holford NH. Clinical pharmacokinetics and pharmacodynamics of warfarin: understanding the dose-effect relationship. Clin Pharmacokinet. 1986;11(6):483–504. doi: 10.2165/00003088-198611060-00005.
    1. Lindenberg M, Kopp S, Dressman JB. Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system. Eur J Pharm Biopharm. 2004;58(2):265–278. doi: 10.1016/j.ejpb.2004.03.001.
    1. Sansone RA, Sansone LA. Warfarin and antidepressants: happiness without hemorrhaging. Psychiatry (Edgmont) 2009;6(7):24–29.
    1. Lennernas H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet. 2003;42(13):1141–1160. doi: 10.2165/00003088-200342130-00005.
    1. European Agency for the Evaluation of Medicinal Products. International Conference on Harmonisation-World Health Organization. Guideline for good clinical practice. ICH Harmonised Tripartite Guideline. Good clinical practice. (2017). Accessed 6 Feb 2017.
    1. World Medical Association. Declaration of Helsinki. Ethical principles for medical research involving human subjects. 52nd WMA General Assembly, Edinburgh, October 2000. Last amended with Note of Clarification on Paragraph 29 by the WMA General Assembly, Washington, 2002; and Note of Clarification on Paragraph 30 by the WMA General Assembly, Tokyo, 2004. . Accessed 6 Feb 2017.
    1. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36(5):1384–1395. doi: 10.2337/dc12-2480.
    1. Medical Dictionary for Regulatory Activities. MedDRA version 17.0 complex changes. (2017). Accessed 6 Feb 2017.
    1. Willems M, Quartero AO, Numans ME. How useful is paracetamol absorption as a marker of gastric emptying? A systematic literature study. Dig Dis Sci. 2001;46(10):2256–2262. doi: 10.1023/A:1011935603893.
    1. Sanaka M, Kuyama Y, Yamanaka M. Guide for judicious use of the paracetamol absorption technique in a study of gastric emptying rate of liquids. J Gastroenterol. 1998;33(6):785–791. doi: 10.1007/s005350050177.
    1. Malm-Erjefalt M, Ekblom M, Vouis J, et al. Effect on the gastrointestinal absorption of drugs from different classes in the biopharmaceutics classification system, when treating with liraglutide. Mol Pharm. 2015;12(11):4166–4173. doi: 10.1021/acs.molpharmaceut.5b00278.
    1. Kothare PA, Soon DK, Linnebjerg H, et al. Effect of exenatide on the steady-state pharmacokinetics of digoxin. J Clin Pharmacol. 2005;45(9):1032–1037. doi: 10.1177/0091270005278806.
    1. Dulaglutide. Summary of product characteristics. (2017). Accessed 6 Feb 2017.
    1. Cilla DD, Jr, Whitfield LR, Gibson DM, et al. Multiple-dose pharmacokinetics, pharmacodynamics, and safety of atorvastatin, an inhibitor of HMG-CoA reductase, in healthy subjects. Clin Pharmacol Ther. 1996;60(6):687–695. doi: 10.1016/S0009-9236(96)90218-0.
    1. Lixisenatide. Summary of product characteristics. (2017). Accessed 6 Feb 2017.
    1. van Can J, Sloth B, Jensen CB, et al. Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults. Int J Obes (Lond). 2014;38(6):784–793. doi: 10.1038/ijo.2013.162.
    1. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6) Lancet. 2009;374(9683):39–47. doi: 10.1016/S0140-6736(09)60659-0.
    1. Buse JB, Nauck M, Forst T, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet. 2013;381(9861):117–124. doi: 10.1016/S0140-6736(12)61267-7.
    1. Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373(9662):473–481. doi: 10.1016/S0140-6736(08)61246-5.
    1. Marre M, Shaw J, Brandle M, et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU) Diabet Med. 2009;26(3):268–278. doi: 10.1111/j.1464-5491.2009.02666.x.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj