Approved & therapeutic
Plecanatide
Trulance
Plecanatide is an orally administered uroguanylin analog and guanylate cyclase-C agonist approved in the US for chronic idiopathic constipation and irritable bowel syndrome with constipation in adults. It is minimally absorbed and acts locally in the intestine.
- Status
- Plecanatide is approved by the U.S. FDA and has official prescribing information.
- Evidence
- Approved labeling. Official prescribing information exists, based on clinical trials in people.
- Half-life
- Not established. Plecanatide is minimally absorbed with negligible systemic availability and plasma concentrations below quantifiable levels in most samples, so no half-life could be calculated. No human excretion studies have been conducted.
- How it's taken
- Oral tablet
- Mechanism
- Other
- Pathways
- Guanylate cyclase-C
How Plecanatide works
Plecanatide is a structural analog of human uroguanylin that agonises guanylate cyclase-C on the luminal surface of the intestinal epithelium. Receptor activation raises intracellular cyclic GMP, which stimulates chloride and bicarbonate secretion into the lumen mainly via the CFTR ion channel, increasing intestinal fluid and accelerating transit. The label also notes that elevated extracellular cyclic GMP has been associated with reduced activity of pain-sensing nerves in animal models of visceral pain. Plecanatide is converted in the gastrointestinal tract to an active metabolite, and both are degraded within the intestinal lumen. Claims that its activity is pH-sensitive in a way that differentiates it regionally from linaclotide come from in-vitro and sponsor literature, not from the FDA label, and have not been shown to produce a clinical difference.
What research has looked at
- In two 12-week placebo-controlled phase 3 chronic idiopathic constipation trials, the primary endpoint (at least 3 complete spontaneous bowel movements in a week plus an increase of at least 1 from baseline in the same week, for at least 9 of 12 weeks including at least 3 of the last 4 weeks) was met in both: 21 percent versus 10 percent on placebo in Study 1 and 21 percent versus 13 percent on placebo in Study 2.
- In two 12-week placebo-controlled phase 3 IBS-with-constipation trials, the FDA overall responder endpoint (at least a 30 percent reduction from baseline in weekly average worst daily abdominal pain AND an increase of at least 1 complete spontaneous bowel movement per week, both met in the same week, for at least 6 of 12 weeks) was met in both, but with different magnitudes: 30 percent versus 18 percent on placebo in Study 3 and 21 percent versus 14 percent on placebo in Study 4.
- A higher dose arm studied alongside the approved dose in all four pivotal trials showed no additional treatment benefit; in the chronic idiopathic constipation trials it also produced a greater incidence of adverse reactions. The label states that the higher dose is not recommended.
- Systemic availability is negligible, so the pharmacologic effect is confined largely to the gut lumen. Neither plecanatide nor its active metabolite inhibited CYP2C9 or CYP3A4, induced CYP3A4, or acted as a substrate or inhibitor of P-glycoprotein or BCRP in vitro.
Evidence level: Approved labeling. Official prescribing information exists, based on clinical trials in people. These are areas studied or reported, not promised effects.
Reported side effects and risks
- Boxed Warning — risk of serious dehydration in pediatric patients: contraindicated in patients less than 6 years of age. In nonclinical studies in young juvenile mice, a single oral dose of plecanatide caused deaths due to dehydration.
- Contraindicated in patients with known or suspected mechanical gastrointestinal obstruction.
- The Boxed Warning also directs avoiding use in patients 6 years to less than 18 years of age; safety and effectiveness have not been established in anyone under 18.
- Diarrhea is the most common adverse reaction and can be severe; the label directs suspending dosing and rehydrating the patient if severe diarrhea occurs. Most cases began within 4 weeks of starting treatment; severe cases occurred within the first 3 days in chronic idiopathic constipation and the first day in IBS with constipation.
- Diarrhea was reported in 5 percent of chronic idiopathic constipation patients and 4.3 percent of IBS-with-constipation patients versus 1 percent on placebo in both programs. Severe diarrhea was reported in 0.6 percent of treated chronic idiopathic constipation patients versus 0.3 percent on placebo, and in 1 percent of treated IBS-with-constipation patients versus 0.1 percent on placebo.
- Discontinuation due to adverse reactions occurred in 4 percent of treated chronic idiopathic constipation patients versus 2 percent on placebo, and 2.5 percent of treated IBS-with-constipation patients versus 0.4 percent on placebo; diarrhea was the most common reason in both.
- Postmarketing reports include hypersensitivity reactions (skin itching, hives, rash) and vomiting.
- Increased liver biochemical tests were reported in a small number of patients across both programs (ALT greater than 5 to 15 times the upper limit of normal; AST greater than 5 times the upper limit of normal in the chronic idiopathic constipation program).
Sources
- PubMed research on Plecanatide · NIH · National Library of Medicine
- DrugBank record for Plecanatide · DrugBank
- Active clinical trials for Plecanatide · U.S. National Library of Medicine
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Plecanatide FAQ
What is Plecanatide?
Plecanatide is an orally administered uroguanylin analog and guanylate cyclase-C agonist approved in the US for chronic idiopathic constipation and irritable bowel syndrome with constipation in adults. It is minimally absorbed and acts locally in the intestine.
How does Plecanatide work?
Plecanatide is a structural analog of human uroguanylin that agonises guanylate cyclase-C on the luminal surface of the intestinal epithelium. Receptor activation raises intracellular cyclic GMP, which stimulates chloride and bicarbonate secretion into the lumen mainly via the CFTR ion channel, increasing intestinal fluid and accelerating transit. The label also notes that elevated extracellular cyclic GMP has been associated with reduced activity of pain-sensing nerves in animal models of visceral pain. Plecanatide is converted in the gastrointestinal tract to an active metabolite, and both are degraded within the intestinal lumen. Claims that its activity is pH-sensitive in a way that differentiates it regionally from linaclotide come from in-vitro and sponsor literature, not from the FDA label, and have not been shown to produce a clinical difference.
Is Plecanatide FDA approved?
Yes. Plecanatide is approved by the U.S. FDA and has official prescribing information. Evidence level: approved labeling. Official prescribing information exists, based on clinical trials in people.
How is Plecanatide taken?
Oral tablet.
What side effects have been reported with Plecanatide?
Reported in the sources: Boxed Warning — risk of serious dehydration in pediatric patients: contraindicated in patients less than 6 years of age. In nonclinical studies in young juvenile mice, a single oral dose of plecanatide caused deaths due to dehydration; Contraindicated in patients with known or suspected mechanical gastrointestinal obstruction; The Boxed Warning also directs avoiding use in patients 6 years to less than 18 years of age; safety and effectiveness have not been established in anyone under 18; Diarrhea is the most common adverse reaction and can be severe; the label directs suspending dosing and rehydrating the patient if severe diarrhea occurs. Most cases began within 4 weeks of starting treatment; severe cases occurred within the first 3 days in chronic idiopathic constipation and the first day in IBS with constipation; Diarrhea was reported in 5 percent of chronic idiopathic constipation patients and 4.3 percent of IBS-with-constipation patients versus 1 percent on placebo in both programs. Severe diarrhea was reported in 0.6 percent of treated chronic idiopathic constipation patients versus 0.3 percent on placebo, and in 1 percent of treated IBS-with-constipation patients versus 0.1 percent on placebo; Discontinuation due to adverse reactions occurred in 4 percent of treated chronic idiopathic constipation patients versus 2 percent on placebo, and 2.5 percent of treated IBS-with-constipation patients versus 0.4 percent on placebo; diarrhea was the most common reason in both; Postmarketing reports include hypersensitivity reactions (skin itching, hives, rash) and vomiting; Increased liver biochemical tests were reported in a small number of patients across both programs (ALT greater than 5 to 15 times the upper limit of normal; AST greater than 5 times the upper limit of normal in the chronic idiopathic constipation program).
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