GC-C agonist · constipation, IBS-C
A prescription tablet for adults with chronic idiopathic constipation or irritable bowel syndrome with constipation (IBS-C). It is a synthetic peptide modelled on uroguanylin, a natural gut peptide that helps control fluid in the intestine. In the US it is marketed as Trulance.
Plecanatide is a structural analog of human uroguanylin. Like the natural hormone, it binds guanylate cyclase-C (GC-C), a receptor on the inner surface of the intestinal lining, and it acts locally there1. Switching on GC-C raises levels of a messenger molecule, cyclic GMP, inside and outside the lining cells. Inside the cells, cyclic GMP opens the CFTR channel, so chloride and bicarbonate move into the gut and water follows. Stools become softer and move through faster1. Higher cyclic GMP outside the cells has been linked to calmer pain-sensing nerves in animal models of gut pain, which may be relevant to the abdominal pain of IBS-C1.
Approval rests on four 12-week, placebo-controlled phase 3 trials in adults1. In one chronic idiopathic constipation trial of 1,394 patients, 21% on plecanatide were durable responders for complete spontaneous bowel movements versus 10% on placebo, and bowel-movement frequency and secondary measures also improved2. Two identical IBS-C trials randomized 2,189 adults. Overall responders, meaning less abdominal pain plus more complete bowel movements, were 21.5% to 30.2% with plecanatide versus 14.2% to 17.8% with placebo3. The FDA label notes that a higher dose in these trials added no benefit, and in the constipation trials it caused more side effects; symptoms generally returned to baseline within two weeks of stopping1.
An open-label study followed 2,272 IBS-C patients for up to 53 weeks on that higher dose and reported a side-effect profile similar to the 12-week trials4.
FDA-approved in 2017 as Trulance for chronic idiopathic constipation in adults; Drugs@FDA records the irritable bowel syndrome with constipation indication being added in 20181. It is marketed by Salix.
Per the FDA label, diarrhea is the most common side effect (5% vs 1% on placebo in the constipation trials). Most cases began within four weeks, and severe diarrhea occurred in about 0.6% of patients. Less common effects include sinusitis, upper respiratory infection, bloating, gas and abdominal tenderness. A boxed warning covers serious dehydration in children: it is contraindicated under age 6 because young juvenile mice died of dehydration, and should be avoided under 18. Known or suspected bowel obstruction is also a contraindication1.
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