No Dose Adjustment is Recommended for Digoxin, Warfarin, Atorvastatin or a Combination Oral Contraceptive When Coadministered with Dulaglutide
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of type 2 diabetes mellitus are known to delay gastric emptying (GE). The potential effect of the GLP-1 RA dulaglutide on the pharmacokinetics (PK) of four orally administered drugs and on the pharmacodynamic (PD) effect of warfarin was investigated.
In four separate clinical pharmacology studies, digoxin, warfarin, atorvastatin and Ortho-Cyclen® were orally administered to healthy subjects with and without a subcutaneous dose of dulaglutide 1.5 mg. The effect of dulaglutide coadministration was assessed based on the PK parameters of key analytes. For warfarin PD, the effect of dulaglutide on the international normalized ratio (INR) was evaluated.
Areas under the concentration–time curves (AUCs) with and without dulaglutide were similar for all analytes except atorvastatin, where it was reduced by 21%. Maximum concentrations (Cmax) were generally lower following coadministration with dulaglutide, with statistically significant reductions (90% confidence intervals of geometric least squares means ratios outside 0.80–1.25) for all analytes except R-warfarin. For all analytes, there was a general trend for the time to Cmax (tmax) to increase following coadministration with dulaglutide. For warfarin, dulaglutide coadministration had no statistically significant effect on the maximum INR (INRmax); however, a 2% increase in area under the INR curve (AUCINR) was observed.
Dulaglutide did not affect the absorption of the tested medications to a clinically relevant degree. Based on the PK and PD evaluations, no dose adjustments for digoxin, warfarin, atorvastatin and Ortho-Cyclen® are recommended when coadministered with dulaglutide.
Clinical trial registration numbers
NCT01458210, NCT01436201, NCT01432938, and NCT01250834.
- 1.Trulicity (prescribing information). Lilly USA, LLC, Indianapolis; 2014. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/125469Orig1s000Lbl.pdf. Accessed 1 Sep 2016.
- 2.Trulicity (summary of product characteristics). Eli Lilly Nederland BV, Utrecht; 2014. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002825/WC500179470.pdf. Accessed 21 Oct 2016.
- 12.Meier JJ, Gallwitz B, Salmen S, Goetze O, Holst JJ, Schmidt WE, et al. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes. J Clin Endocrinol Metab. 2003;88(6):2719–25.CrossRefPubMedGoogle Scholar
- 14.Meier JJ, Rosenstock J, Hincelin-Méry A, Roy-Duval C, Delfolie A, Coester HV, et al. Contrasting effects of lixisenatide and liraglutide on postprandial glycemic control, gastric emptying, and safety parameters in patients with type 2 diabetes on optimized insulin glargine with or without metformin: a randomized, open-label trial. Diabetes Care. 2015;38(7):1263–73.CrossRefPubMedGoogle Scholar
- 16.Loghin C, de la Peña A, Cui X, Chien J. Gastric emptying effects of once weekly dulaglutide in patients with type 2 diabetes mellitus (poster). Presented at the American Association of Clinical Endocrinologists, 23rd annual scientific and clinical congress, 14–18 May 2014, Las Vegas.Google Scholar
- 18.Lanoxin (prescribing information). Covis Pharmaceuticals Inc.; 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/009330s030lbl.pdf.Accessed 21 Oct 2016.
- 19.Coumadin (prescribing information). Bristol-Myers Squibb Company; 2016. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/009218s116lbl.pdf. Accessed 21 Oct 2016.
- 24.Lipitor (prescribing information). Pfizer Inc.; 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020702s065lbl.pdf. Accessed 21 Oct 2016.
- 25.Ortho-Cyclen (prescribing information). Janssen Pharmaceuticals, Inc.; 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019653s056,019697s052,021690s001lbl.pdf. Accessed 21 Oct 2016.
- 32.Kothare PA, Seger ME, Northrup J, Mace K, Mitchell MI, Linnebjerg H. Effect of exenatide on the pharmacokinetics of a combination oral contraceptive in healthy women: an open-label, randomised, crossover trial. BMC Clin Pharmacol. 2012;12(8):1–9.Google Scholar
- 33.US FDA. Guidance for industry. Drug interaction studies—study design, data analysis, implications for dosing, and labeling recommendations. US FDA; 2012.Google Scholar