Linaclotide, Novel Therapy for the Treatment of Chronic Idiopathic Constipation and Constipation-Predominant Irritable Bowel Syndrome
First Online: 20 February 2013 Received: 07 November 2012 DOI:
10.1007/s12325-013-0012-9 Cite this article as: Vazquez-Roque, M.I. & Bouras, E.P. Adv Therapy (2013) 30: 203. doi:10.1007/s12325-013-0012-9 Abstract
Chronic constipation (CC) and irritable bowel syndrome with constipation (IBS-C) are common gastrointestinal (GI) disorders. Current treatment options, either prescription or nonprescription medications, have limited efficacy in a subset of patients. There is significant demand for more efficacious medications for the treatment of CC and IBS-C. Linaclotide, a secretagogue, has a novel mechanism of action designed to treat patients with CC and IBS-C. It has a low oral bioavailability with negligible systemic side effects, and it acts locally in the intestinal lumen. In several clinical trials, in health and disease, linaclotide has demonstrated durable efficacy and safety in CC and IBS-C. Linaclotide received approval by the Federal Drug Administration in August 2012 to treat chronic idiopathic constipation and IBS-C.
Keywords Constipation Gastroenterology Guanylate cyclase C Guanylin Irritable bowel syndrome Linaclotide Uroguanylin References
Higgins PD, Johanson JF. Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol. 2004;99:750–759.
Choung RS, Locke GR, 3rd, Schleck CD, et al. Cumulative incidence of chronic constipation: a population-based study 1988–2003. Aliment Pharmacol Ther. 2007;26:1521–1528.
Vazquez Roque M, Camilleri M. Linaclotide, a synthetic guanylate cyclase C agonist, for the treatment of functional gastrointestinal disorders associated with constipation. Expert Rev Gastroenterol Hepatol. 2011;5:301–310.
Everhart JE, Go VL, Johannes RS, et al. A longitudinal survey of self-reported bowel habits in the United States. Dig Dis Sci. 1989;34:1153–1162.
Sonnenberg A, Koch TR. Physician visits in the United States for constipation: 1958 to 1986. Dig Dis Sci. 1989;34:606–611.
Martin BC, Barghout V, Cerulli A. Direct medical costs of constipation in the United States. Manag Care Interface. 2006;19:43–49.
Bongers ME, Benninga MA, Maurice-Stam H, et al. Health-related quality of life in young adults with symptoms of constipation continuing from childhood into adulthood. Health Qual Life Outcomes 2009;7:20.
Wang JP, Duan LP, Ye HJ, et al. [Assessment of psychological status and quality of life in patients with functional constipation]. Zhonghua Nei Ke Za Zhi. 2008;47:460–463. In Chinese.
Sun SX, Dibonaventura M, Purayidathil FW, et al. Impact of chronic constipation on health-related quality of life, work productivity, and healthcare resource use: an analysis of the National Health and Wellness Survey. Dig Dis Sci. 2011;56:2688–2695.
Drossman DA, Camilleri M, Mayer EA, et al. AGA technical review on irritable bowel syndrome. Gastroenterology. 2002;123:2108–2131.
Spiegel BM. The burden of IBS: looking at metrics. Curr Gastroenterol Rep. 2009;11:265–269.
Vazquez Roque M, Camilleri M. Velusetrag. Drugs Future. 2011;36:447–454.
Camilleri M, Kerstens R, Rykx A, et al. A placebocontrolled trial of prucalopride for severe chronic constipation. N Engl J Med. 2008;358:2344–2354.
Wong BS, Camilleri M, McKinzie S, et al. Effects of A3309, an ileal bile acid transporter inhibitor, on colonic transit and symptoms in females with functional constipation. Am J Gastroenterol. 2011;106:2154–2164.
Lucas KA, Pitari GM, Kazerounian S, et al. Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev. 2000;52:375–414.
Bryant AP, Busby RW, Bartolini WP, et al. Linaclotide is a potent and selective guanylate cyclase C agonist that elicits pharmacological effects locally in the gastrointestinal tract. Life Sci. 2010;86:760–765.
Harris LA, Crowell MD. Linaclotide, a new direction in the treatment of irritable bowel syndrome and chronic constipation. Curr Opin Mol Ther. 2007;9:403–410.
Schulz S, Lopez MJ, Kuhn M, et al. Disruption of the guanylyl cyclase-C gene leads to a paradoxical phenotype of viable but heat-stable enterotoxin-resistant mice. J Clin Invest. 1997;100:1590–1595.
Busby RW, Bryant AP, Cordero EA, et al. The molecular target of MD-1100 is guanylate cyclase-C (GC-C), an apical receptor on intestinal epithelial cell. Gastroenterology. 2005;128:A464.
Busby RW, Bryant AP, Bartolini WP, et al. Linaclotide, through activation of guanylate cyclase C, acts locally in the gastrointestinal tract to elicit enhanced intestinal secretion and transit. Eur J Pharmacol. 2010;649:328–335.
Bryant AP, Busby RW, Cordero EA, et al. MD-1100, a therapeutic agent in development for the treatment of IBS-C, enhances intestinal secretion and transit, decreases visceral pain and is minimally absorbed in rats. Gastroenterology. 2005;128:A464.
Bryant AP, Busby RW, Cordero EA, et al. The characterization of an active metabolite of MD-1100, a therapeutic agent in development for the treatment of IBS-C and chronic constipation. Gastroenterology. 2006;130:T2034.
Eutamene H, Bradesi S, Larauche M, et al. Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain. Neurogastroenterol Motil. 2010;22:312–e384.
Castro JHA, Hughes PA, Martin C, et al. Mechanism of action for linaclotide induced abdominal pain relief. Gastroenterology. 2012;142:S699.
Brady S. Microbia succesfully completes phase IA trial of MD-1100 for IBS-C and other GI disorders. 2005. Available at:
. Accessed Sep 1 2012.
Currie MG, Kurtz CB, Mahajan-Miklos S, et al. Effects of single dose administration of MD-1100 on safety, tolerability, exposure, and stool consistency in healthy subjects. Am J Gastroenterol. 2005;100:S328.
Kurtz CB, Fitch DA, Busby RW, et al. Effects of multidose administration of MD-1100 on safety, tolerability, exposure, and pharmacodynamics in healthy subjects. Gastroenterology. 2006;130:A–26. Abstract 132.
Andresen V, Camilleri M, Busciglio IA, et al. Effect of 5 days linaclotide on transit and bowel function in females with constipation-predominant irritable bowel syndrome. Gastroenterology. 2007;133:761–768.
Johnston JM, Kurtz CB, Drossman DA, et al. Pilot study on the effect of linaclotide in patients with chronic constipation. Am J Gastroenterol. 2009;104:125–132.
Lembo AJ, Kurtz CB, Macdougall JE, et al. Efficacy of linaclotide for patients with chronic constipation. Gastroenterology. 2010;138:886–895.e1.
Johnston JM, Kurtz CB, Macdougall JE, et al. Linaclotide improves abdominal pain and bowel habits in a phase IIb study of patients with irritable bowel syndrome with constipation. Gastroenterology. 2010;139:1877–1886.e2.
Lembo AJ, Schneier HA, Shiff SJ, et al. Two randomized trials of linaclotide for chronic constipation. N Engl J Med. 2011;365:527–536.
Rao S, Lembo AJ, Shiff SJ, et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 2012;107:1714–1724.
Chey WD, Lembo AJ, Lavins BJ, et al. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebocontrolled trial to evaluate efficacy and safety. Am J Gastroenterol. 2012;107:1702–1712.
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