GC-C agonist · IBS-C and constipation
Linaclotide is a small peptide, taken by mouth as a capsule, that works on the inner surface of the gut and is barely absorbed into the blood. It is structurally related to guanylin and uroguanylin, the intestine's own fluid-regulating hormones, and is a prescription treatment for constipation-predominant irritable bowel syndrome (IBS-C) and chronic constipation.
Linaclotide and its active metabolite act locally on the inner (luminal) lining of the intestine, where they bind guanylate cyclase-C (GC-C)1. Activating GC-C raises cyclic GMP inside the cells, which opens the CFTR chloride channel; chloride and bicarbonate move into the gut, water follows, and transit speeds up1. Cyclic GMP also rises outside the cells, and in an animal model of visceral pain linaclotide reduced the activity of pain-sensing nerves through this extracellular cGMP, a proposed explanation for the drop in abdominal pain seen in IBS-C trials1. It is minimally absorbed, with blood levels too low to measure, so it acts locally in the intestine1.
In a 26-week Phase 3 trial of 804 adults with IBS-C, 33.7% on linaclotide met the FDA's combined responder endpoint (less abdominal pain plus more complete bowel movements in the same week, for at least half of the first 12 weeks) versus 13.9% on placebo; bloating, straining and stool form also improved2.
In two 12-week trials of 1,276 people with chronic constipation, 16-21% reached the main bowel-movement endpoint versus 3-6% on placebo3. Diarrhea was the side effect that set it apart from placebo, leading about 4-5% of linaclotide users to stop, compared with 0.2% on placebo in the IBS-C trial2,3. The label adds pediatric studies supporting use in children with IBS-C or functional constipation1.
The FDA approved linaclotide in 2012 as Linzess (now AbbVie) for IBS-C and chronic idiopathic constipation in adults; the label now also covers IBS-C in children 7 and older and functional constipation in children 2 and older1. Generic linaclotide capsules have also been approved.
Diarrhea is the most common side effect and can be severe; the label says to suspend treatment and rehydrate if it is. Abdominal pain, gas and bloating are also common in adults. A boxed warning contraindicates use under age 2, because in newborn mice a single exposure caused deaths from dehydration. It must not be used with known or suspected mechanical bowel obstruction1.
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