Plecanatide
Trulance — a GC-C agonist peptide (originally Synergy Pharmaceuticals, now Salix / Bausch Health) FDA-approved January 2017 for CIC and January 2018 for IBS-C. Modeled on uroguanylin (the more pH-sensitive of the two endogenous GC-C ligands), which its developers proposed gives it a more physiologic region-specific activity profile than linaclotide.
A 16-residue synthetic peptide GC-C agonist developed by Synergy Pharmaceuticals (later acquired by Bausch Health's Salix Pharmaceuticals division) and marketed as Trulance. Distinguished from linaclotide by a single amino acid difference at position 3 (Asp vs Glu) that makes plecanatide more similar to uroguanylin than to guanylin. This gives plecanatide a pH-sensitive activity profile — more active at the slightly acidic pH of the proximal small intestine than at neutral pH — which its developers proposed would produce more physiologic, region-selective GC-C activation than linaclotide. FDA-approved January 2017 for chronic idiopathic constipation in adults and January 2018 for IBS-C in adults. Clinically, the efficacy and safety profiles of linaclotide and plecanatide appear broadly similar; no head-to-head trial has demonstrated clear superiority of either agent.
Mechanism of action
Binds GC-C on the luminal surface of intestinal epithelial cells. Mechanism is otherwise identical to linaclotide: GC-C activation → intracellular cGMP rise → PKG II activation → CFTR phosphorylation → luminal chloride and bicarbonate secretion → osmotic water movement into lumen. Proposed pharmacodynamic distinction from linaclotide is pH-sensitive activity favoring the proximal small intestine (where luminal pH is slightly acidic) over the more distal gut — a feature derived from plecanatide's closer structural relationship to uroguanylin. Clinical translation of this proposed region-selective pharmacology has not been convincingly demonstrated in head-to-head trials.
Primary uses
- Chronic idiopathic constipation in adults (FDA-approved 2017)
- Irritable bowel syndrome with constipation in adults (FDA-approved 2018)
Typical dosing
Adults: 3 mg orally once daily with or without food. Can be administered whole or as a sprinkle on applesauce or in water. Contraindicated in patients <6 years. Most common adverse event is diarrhea (leading to discontinuation in ~4% of patients). Approved dose (3 mg) is higher than linaclotide (145–290 mcg) because of plecanatide's different binding affinity and pH-dependent activity profile.
Regulatory status
FDA-approved January 19, 2017 (Synergy Pharmaceuticals, subsequently acquired by Salix Pharmaceuticals / Bausch Health) for chronic idiopathic constipation in adults. Label expanded January 24, 2018 to include irritable bowel syndrome with constipation in adults. Boxed warning for serious dehydration in pediatric patients <6 years and contraindication in patients <6.
References
- [fda-label] Trulance (plecanatide) Prescribing Information. Salix Pharmaceuticals, Bausch Health. Initial U.S. Approval: 2017.
- [pubmed] Miner PB Jr, et al. "A randomized phase III clinical trial of plecanatide, a uroguanylin analog, in patients with chronic idiopathic constipation." Am J Gastroenterol, 2017;112:613-621.
- [pubmed] Brenner DM, et al. "Efficacy, safety, and tolerability of plecanatide in patients with irritable bowel syndrome with constipation: results of two phase 3 randomized clinical trials." Am J Gastroenterol, 2018;113:735-745.
Related peptides
This entry is for educational purposes only and does not constitute medical advice. Dosing information reflects published regulatory or research data and is not a recommendation. Many compounds described here are not approved for human use in the United States. Consult a licensed medical professional before considering any peptide therapy.