Linaclotide: a guanylate cyclase type-C agonist for the treatment of constipation-predominant irritable bowel syndrome and chronic constipation

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From: Formulary(Vol. 47, Issue 1)
Publisher: Intellisphere, LLC
Document Type: Drug overview; Report
Length: 4,339 words
Lexile Measure: 1850L

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Constipation-predominant irritable bowel syndrome (IBS-C) and chronic constipation affect millions of Americans. Patients diagnosed with these conditions experience adverse symptoms that can have a negative impact on their quality of life. Use of agents currently available for treatment is not supported by well-controlled clinical studies. A new drug application for linaclotide, an orally administered guanylate cyclase type-C receptor agonist for treatment of IBS-C and chronic constipation, was submitted to the US Food and Drug Administration (FDA) with a target action date of June 2012. In clinical trials, linaclotide was dosed once daily, had minimal systemic absorption, lacked major drug interactions, and did not require dosage adjustment in patients with renal or hepatic impairment. Studies demonstrated linaclotide to be superior to placebo in achieving primary efficacy end points of at least 30% abdominal pain reduction, at least 3 complete spontaneous bowel movements, and an increase of at least 1 complete spontaneous bowel movement per week compared with baseline. The most common adverse effect was diarrhea. Linaclotide seems to be a promising new agent for the management of IBS-C and chronic constipation. (Formulary. 2012; 47:15-22.)


Irritable bowel syndrome (IBS) is a gastrointestinal (GI) disorder characterized by chronic abdominal pain and altered bowel habits that cannot be attributed to any apparent structural or physiologic cause. (1) IBS can lead to reduced health-related quality of life (QOL) and diminished functional status, as well as disproportionate consumption of healthcare resources. The disorder is categorized into 3 subtypes: diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), and mixed IBS (IBS-M); IBS-D and IBS-M are the most common types. (1) IBS is thought to occur due to altered intestinal function stemming from multiple causes. Visceral hypersensitivity can result from problems in processing of neural signals, which may occur due to genetic factors, changes in motility, inflammation, infection, stress, and psychological factors. (2)

Constipation affects approximately 2% to 27% of patients in Western countries and occurs more commonly in women than men; the annual cost of agents to relieve its symptoms is hundreds of millions of dollars. (3) Constipation is characterized by a decrease in the frequency of bowel movements leading to output of hard and dry stool. (3) Independent of number of bowel movements, patients generally describe a broad range of symptoms, including straining and a feeling of incomplete evacuation. Constipation can be caused by medications; health conditions, including GI tract and neurologic disorders; and lifestyle choices. (4) Medications commonly associated with constipation include opioids; non-dihydropyridine calcium channel blockers; antacids containing calcium and aluminum; tricyclic antidepressants; and anticholinergics, including antihistamines. (2)

Patients with IBS-C and chronic constipation are treated predominantly with symptom management and self-care. For both types of constipation, dietary fiber is usually the first line of therapy for symptom relief. (1,4) When dietary modification is unsuccessful, pharmacologic methods may be initiated. (2)

The American Gastroenterological Association recommends use of an osmotic laxative (specifically, magnesium hydroxide) as a first-line pharmacologic agent for constipation. (4) Other osmotic agents such as sorbitol, lactulose, and polyethylene glycol can be tried if dietary...

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Gale Document Number: GALE|A281375130