The online version of this article (doi:10.1007/s40262-016-0410-7) contains supplementary material, which is available to authorized users.
This analysis used a population pharmacokinetic approach to identify covariates that influence plasma exposure of liraglutide 3.0 mg, a glucagon-like peptide-1 (GLP-1) receptor agonist approved for weight management in overweight and obese individuals.
Samples for pharmacokinetic analysis were drawn at weeks 2, 12 and 28 of the phase IIIa SCALE Obesity and Prediabetes (N = 2339) and SCALE Diabetes (N = 584) trials. Dose proportionality of liraglutide in obese subjects was investigated using data from a phase II dose-finding study (N = 331).
Dose-proportional exposure of liraglutide up to and including 3.0 mg was confirmed. Body weight and sex influenced exposure of liraglutide 3.0 mg, while age ≥70 years, race, ethnicity and baseline glycaemic status did not. Compared with a reference subject weighing 100 kg, exposure of liraglutide 3.0 mg was 44 % lower for a subject weighing 234 kg (90 % CI 41–47), 41 % higher for a subject weighing 60 kg (90 % CI 37–46), and 32 % higher (90 % CI 28–35) in females than males with the same body weight. Neither injection site nor renal function significantly influenced exposure of liraglutide 3.0 mg (post hoc analysis).
Population pharmacokinetics of liraglutide up to and including 3.0 mg daily in overweight and obese adults demonstrated dose-proportional exposure, and limited effect of covariates other than sex and body weight. These findings were similar to those previously observed with liraglutide up to 1.8 mg in subjects with type 2 diabetes mellitus. Further analysis of exposure–response relationship and its effect on dose requirements is addressed in a separate publication.
Supplementary material 1 (PDF 620 kb)40262_2016_410_MOESM1_ESM.pdf
Saxenda ® (liraglutide) highlights of prescribing information. Novo Nordisk Inc. 2015. Available at: http://www.novo-pi.com/saxenda.pdf. Accessed Oct 2015.
Saxenda ® (liraglutide) summary product information. Novo Nordisk Canada Inc. 2015. Available at: http://www.novonordisk.ca/content/dam/Canada/AFFILIATE/www-novonordisk-ca/OurProducts/PDF/Saxenda_PM_English.pdf. Accessed Aug 2015.
Saxenda ® (liraglutide) summary product information. European Medicines Agency. 2015. Available at: http://ec.europa.eu/health/documents/community-register/2015/20150323131125/anx_131125_en.pdf. Accessed Sep 2015.
Federación Mexicana de Diabetes A.C. COFEPRIS approved the first treatment for chronic management of obesity in Mexico [press release], Feb 2015. Available at: http://fmdiabetes.org/aprueba-la-cofepris-primer-tratamiento-para-el-manejo-cronico-de-la-obesidad-en-mexico/. Accessed Nov 2015.
van Can CJ, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WH. 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;38:784–93. CrossRef
Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, American College of Cardiology/American Heart Association Task Force on Practice Guidelines, Obesity Society, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol. 2014;63:2985–3023. CrossRefPubMed
Collaboration Prospective Studies, Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, et al. Body-mass index and cause-specific mortality in 900,000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009;373:1083–96. CrossRef
Phelan S, Kanaya AM, Subak LL, Hogan PE, Espeland MA, Wing RR, Action for Health in Diabetes (Look AHEAD) Research Group, et al. Prevalence and risk factors for urinary incontinence in overweight and obese diabetic women: action for health in diabetes (look ahead) study. Diabetes Care. 2009;32:1391–7. CrossRefPubMedPubMedCentral
Jia H, Lubetkin EI. The impact of obesity on health-related quality-of-life in the general adult US population. J Public Health (Oxf). 2005;27:156–64. CrossRef
US FDA. Guidance for industry. Developing products for weight management. Draft Guidance. 2007. Available at: http://www.fda.gov/downloads/Drugs/Guidances/ucm071612.pdf. Accessed June 2015.
US FDA. Guidance for industry. Population pharmacokinetics. 2009. Available at: http://www.fda.gov/downloads/Drugs/Guidances/UCM072137.pdf. Accessed June 2015.
EMA. Guideline on the investigation of drug interactions. 2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf. Accessed June 2015.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration, et al. A new equation to estimate glomerular filtration rate. CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). Ann Intern Med. 2009;150:604–12. CrossRefPubMedPubMedCentral
World Medical Association. Declaration of Helsinki: ethical principles for medical research involving human subjects. 2013. Available at: http://www.wma.net/en/30publications/10policies/b3/. Accessed June 2015.
International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Good Clinical Practice. 1996. Available at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf. Accessed June 2015.
Jacobsen LV, Flint A, Olsen AK, Ingwersen SH. Liraglutide in type 2 diabetes mellitus: clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. doi: 10.1007/s40262-015-0343-6. Epub 23 Nov 2015.
Malm-Erjefält M, Bjørnsdottir I, Vanggaard J, Helleberg H, Larsen U, Oosterhuis B, et al. Metabolism and excretion of the once-daily human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutralendopeptidase. Drug Metab Dispos. 2010;38:1944–53. CrossRefPubMed
Victoza ® (liraglutide) Summary of product characteristics. 2014. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001026/WC500050017.pdf. Accessed Aug 2015.
Victoza ® (liraglutide) Highlights of prescribing information. 2010. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022341lbl.pdf. Accessed Sep 2015.
- Liraglutide 3.0 mg for Weight Management: A Population Pharmacokinetic Analysis
Rune V. Overgaard
Kristin C. Petri
Lisbeth V. Jacobsen
Christine B. Jensen
- Springer International Publishing