FDA Approved Healing & Recovery

Linaclotide

also known as: Linzess, Constella (EU), MD-1100, MM-416775

Linzess — a GC-C agonist peptide (Ironwood / AbbVie / Astellas) FDA-approved in August 2012 for IBS-C and chronic idiopathic constipation in adults, with a 2023 pediatric expansion for functional constipation in children 6–17. First-in-class oral peptide that works luminally on intestinal GC-C receptors to stimulate chloride and bicarbonate secretion, accelerate transit, and reduce visceral pain.

A 14-residue synthetic peptide modeled on the endogenous GC-C ligands guanylin and uroguanylin, with three intramolecular disulfide bonds stabilizing a compact fold. Developed by Microbia (later Ironwood Pharmaceuticals) and co-commercialized with AbbVie (US) and Astellas (Japan / Asia) under the brand name Linzess. FDA-approved in August 2012 for IBS-C and CIC in adults; pediatric label expansion for functional constipation in children aged 6–17 in June 2023. Acts luminally on GC-C receptors in the intestinal epithelium, raising intracellular cGMP, activating the CFTR chloride channel, and stimulating chloride and bicarbonate secretion into the intestinal lumen — accelerating transit and softening stool. The cGMP increase also has local visceral-analgesic effects on afferent nociceptive fibers, which contribute to the IBS-C abdominal-pain benefit. Essentially not absorbed systemically; action is entirely luminal.

Mechanism of action

Binds guanylate cyclase-C (GC-C) on the luminal (apical) surface of intestinal epithelial cells, mimicking the endogenous ligands guanylin and uroguanylin. Activation of GC-C increases intracellular cGMP, which activates protein kinase G II (PKG II) and phosphorylates the CFTR chloride channel, increasing luminal secretion of chloride and (via anion-exchange transporters) bicarbonate. Water follows the osmotic gradient into the lumen, softening stool and accelerating transit. Increased cGMP also has a direct visceral-analgesic effect on submucosal afferent nociceptive neurons, which accounts for linaclotide's effect on IBS-C abdominal pain. Mechanism is luminal and local; systemic absorption is negligible.

Primary uses

Irritable bowel syndrome with constipation (IBS-C) in adults (FDA-approved)
Chronic idiopathic constipation (CIC) in adults (FDA-approved)
Functional constipation in pediatric patients aged 6–17 (FDA-approved 2023)

Typical dosing

72, 145, or 290 mcg once daily on an empty stomach (oral)

Adult CIC: 145 mcg once daily (72 mcg option available for patients who prefer a lower starting dose). Adult IBS-C: 290 mcg once daily. Pediatric functional constipation (6–17): 72 mcg once daily. Take at least 30 minutes before the first meal of the day. Contraindicated in patients <2 years. Most common adverse event is diarrhea (which leads to discontinuation in ~5% of patients).

Regulatory status

FDA-approved August 30, 2012 (Ironwood Pharmaceuticals / Forest Laboratories, now AbbVie) for adults with irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC). Boxed warning for serious dehydration in pediatric patients <2 years and contraindication in patients <2. EMA authorization November 2012 (Constella, Allergan). Pediatric label expansion June 2023 for functional constipation in patients aged 6–17 years (branded Linzess Jr. or same Linzess label depending on formulation).

References

[fda-label] Linzess (linaclotide) Prescribing Information. Ironwood Pharmaceuticals, AbbVie. Initial U.S. Approval: 2012.
[pubmed] Chey WD, et al. "Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety." Am J Gastroenterol, 2012;107:1702-1712.
[pubmed] Lembo AJ, et al. "Two randomized trials of linaclotide for chronic constipation." N Engl J Med, 2011;365:527-536.

Related peptides

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.

Disclaimer

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.