Assessment of Drug–Drug Interactions between Taspoglutide, a Glucagon-Like Peptide-1 Agonist, and Drugs Commonly Used in Type 2 Diabetes Mellitus: Results of Five Phase I Trials
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Background and Objective
Taspoglutide, a glucagon-like peptide-1 agonist, like native glucagon-like peptide-1, delays gastric emptying time and prolongs intestinal transit time, which may alter the pharmacokinetics of concomitantly administered oral drugs. The effect of taspoglutide on the pharmacokinetics of five oral drugs commonly used in patients with type 2 diabetes mellitus was assessed in healthy subjects.
Five clinical pharmacology studies evaluated the potential drug–drug interaction between multiple subcutaneous taspoglutide doses and a single dose of lisinopril, warfarin, and simvastatin and multiple doses of digoxin and an oral contraceptive containing ethinylestradiol and levonorgestrel. The extent of interaction was quantified using geometric mean ratios and 90% confidence intervals for the maximum plasma concentration and area under the plasma concentration–time curve. In addition to pharmacokinetics, pharmacodynamic effects were assessed for warfarin and the oral contraceptive.
Among the tested drugs, the effect of taspoglutide on the pharmacokinetics of simvastatin was most pronounced, on the day of taspoglutide administration, the average exposure to simvastatin was decreased by − 26% and − 58% for the area under the plasma concentration–time curve and maximum plasma concentration, respectively, accompanied by an increase in average exposure to its active metabolite, simvastatin β-hydroxy acid (+ 74% and + 23% for area under the plasma concentration–time curve and maximum plasma concentration, respectively). Although statistically significant changes in exposure were observed for other test drugs, the 90% confidence intervals for the geometric mean ratio for maximum plasma concentration and area under the plasma concentration–time curve were within the 0.7–1.3 interval. No clinically relevant changes on coagulation (for warfarin) and ovulation-suppressing activity (for the oral contraceptive) were apparent.
Overall, multiple doses of taspoglutide did not result in changes in the pharmacokinetics of digoxin, an oral contraceptive containing ethinylestradiol and levonorgestrel, lisinopril, warfarin, and simvastatin that would be considered of clinical relevance. Therefore, no dose adjustments are warranted upon co-administration.
The authors thank Elke Zwanziger, Katja Heinig, Jon Talbot, Christelle Vistuer, and Nathalie Lambert for providing scientific review, operational, and technical support.
Compliance with Ethical Standards
This study was funded by F. Hoffmann-La Roche Ltd.
Conflict of interest
Katrijn Bogman, Jochen Brumm, Carsten Hofmann, Mylène Giraudon, Markus Niggli, Carolina Sturm-Pellanda, Annette Sauter, Stefan Sturm, and Christophe Schmitt are employees of F. Hoffmann-La Roche Ltd. Katrijn Bogman, Carsten Hofmann, Carolina Sturm-Pellanda, Annette Sauter, Stefan Sturm, Christophe Schmitt, and Bernhard Mangold are shareholders of F. Hoffmann-La Roche Ltd. Bernhard Mangold was an employee of F. Hoffmann-La Roche Ltd. at the time the studies were conducted and reported.
- 3.Raccah D. Safety and tolerability of glucagon-like peptide-1 receptor agonists: unresolved and emerging issues. Expert Opin Drug Saf. 2017;16(2):227–36.Google Scholar
- 7.Tran KL, Park YI, Pandya S, Muliyil NJ, Jensen BD, Huynh K, Nguyen QT. Overview of glucagon-like peptide-1 receptor agonists for the treatment of patients with type 2 diabetes. Am Health Drug Benefits. 2017;10(4):178–88.Google Scholar
- 9.Loghin C, de la Pen˜a A, Cui X, Chien J. Gastric emptying effects of once weekly dulaglutide in patients with type 2 diabetes mellitus [poster]. In: 23rd Annual Scientific and Clinical Congress of the American Association of Clinical Endocrinologists; 19 May 2014. https://www.mdlinx.com/endocrinology/conference-abstract.cfm/12181/?nonus=0&searchstring=&coverage_day=0&page=1. Accessed 3 Mar 2019.
- 15.Byetta (exenatide), prescribing information. 2009. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021773s9s11s18s22s25lbl.pdf. Accessed 13 Feb 2019.
- 16.Bydureon (exenatide extended-release), prescribing information. 2012. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022200s000lbl.pdf. Accessed 13 Feb 2019.
- 17.Lyxumia (lixisenatide), summary of product characteristics. 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002445/WC500140401.pdf. Accessed 13 Feb 2019.
- 24.Raz I, Fonseca V, Kipnes M, Durrwell L, Hoekstra J, Boldrin M, Balena R. Efficacy and safety of taspoglutide monotherapy in drug-naive type 2 diabetic patients after 24 weeks of treatment: results of a randomized, double-blind, placebo-controlled phase 3 study (T-Emerge 1). Diabetes Care. 2012;35(3):485–7.CrossRefGoogle Scholar
- 26.Henry RR, Mudaliar S, Kanitra L, Woloschak M, Balena R, T-Emerge 3 Study Group. Efficacy and safety of taspoglutide in patients with type 2 diabetes inadequately controlled with metformin plus pioglitazone over 24 weeks: T-Emerge 3 trial. J Clin Endocrinol Metab. 2012;97(7):2370–9.CrossRefGoogle Scholar
- 28.Nauck M, Horton E, Andjelkovic M, Ampudia-Blasco FJ, Parusel CT, Boldrin M, Balena R, T-Emerge 5 Study Group. Taspoglutide, a once-weekly glucagon-like peptide 1 analogue, vs. insulin glargine titrated to target in patients with type 2 diabetes: an open-label randomized trial. Diabet Med. 2013;30(1):109–13.CrossRefGoogle Scholar
- 29.Pratley RE, Urosevic D, Boldrin M, Balena R, T-Emerge 6 Study Group. Efficacy and tolerability of taspoglutide versus pioglitazone in subjects with type 2 diabetes uncontrolled with sulphonylurea or sulphonylurea-metformin therapy: a randomized, double-blind study (T-Emerge 6). Diabetes Obes Metab. 2013;15(3):234–40.CrossRefGoogle Scholar
- 31.Ratner R, Nauck M, Kapitza C, Asnaghi V, Boldrin M, Balena R. Safety and tolerability of high doses of taspoglutide, a once-weekly human GLP-1 analogue, in diabetic patients treated with metformin: a randomized double-blind placebo-controlled study. Diabet Med. 2010;27(5):556–62.CrossRefGoogle Scholar
- 35.Vickers S, Duncan CA, Chen IW, Rosegay A, Duggan DE. Metabolic disposition studies on simvastatin, a cholesterol-lowering prodrug. Drug Metab Dispos. 1990;18(2):138–45.Google Scholar
- 38.Tsamandouras N, Dickinson G, Guo Y, Hall S, Rostami-Hodjegan A, Galetin A, Aarons L. Development and application of a mechanistic pharmacokinetic model for simvastatin and its active metabolite simvastatin acid using an integrated population PBPK approach. Pharm Res. 2015;32(6):1864–83.CrossRefGoogle Scholar
- 45.Zocor (simvastatin) prescribing information. 2012. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019766s085lbl.pdf. Accessed 13 Feb 2019.