Clinical utility of plecanatide in the treatment of chronic idiopathic constipation

Figures & data

Table 1 Pharmaceutical agents available for the treatment of constipation

Drug name	Mechanism of action	Side effects	Indication
Psyllium (Metamucil), methylcellulose (Citrucel), calcium polycarbophil (FiberCon), wheat dextrin (Benefibre)	Bulking agents: indigestible fiber forms a soft bulky stool to stimulate motility	Bloating, intestinal gas, cramping, increased constipation	CIC, OIC, IBS-C
PEG3350, lactulose, sorbitol magnesium salts (milk of magnesia)	Osmotic laxatives: draw water into the bowel from the intestinal lumen and soften the stool	Electrolyte imbalance, leading to increased thirst and dehydration, nausea, diarrhea	Occasional constipation
Senna (Senokot) Bisacodyl (Ex-Lax, Dulcolax)	Stimulant laxatives: induce propagated colonic contractions to accelerate transit; increase intestinal fluid accumulation and laxation by altering water and electrolyte secretion	Abdominal pain or cramping, vomiting, electrolyte imbalance with extended use	Occasional constipation
Lubiprostone (Amitiza)	Secretagogue: activates ClC-2 chloride channels to increase secretion	Nausea (30%), diarrhea and headache (13%), abdominal pain, post market reports of tachycardia, syncope and hypotension	CIC, OIC, IBS-C
Prucalopride	Prokinetics: high affinity serotonin 4 receptor agonist	Not approved in the USA due to ischemic events; other side effects include nausea (17%), diarrhea (12.1%), abdominal pain	CIC

Abbreviations: CIC, chronic idiopathic constipation; OIC, opioid-induced constipation; IBS-C, irritable bowel syndrome with constipation.

Figure 1 The cyclic guanosine monophosphate (cGMP) signaling axis in the intestinal epithelium. Guanylyl cyclase C (GC-C) receptors expressed on the apical surface of intestinal epithelial cells produce cGMP from guanosine triphosphate (GTP) when bound by endogenous hormones uroguanylin (Uro) and guanylin (Gn). The synthetic peptide agonist plecanatide (Ple) mimics Uro, whereas linaclotide (Lin) mimics the heat-stable toxin from enterotoxigenic bacteria (STa). Elevated cGMP levels increase luminal solutes by blocking Na⁺ uptake through the sodium-hydrogen exchanger (NHE), and by activating type 2 cGMP-dependent protein kinase (PKG2), which in turn activates the cystic fibrosis transmembrane conductance regulator (CFTR). Several mechanisms restore equilibrium, including cGMP-specific phosphodiesterase 5 (PDE5) that hydrolyzes cGMP to inactive GMP, and by export of cGMP by multidrug resistance protein 4 (MDR4). Blockade of H⁺ exchange and secretion of HCO₃⁻ by the chloride-bicarbonate exchanger (Cl⁻/HCO3) increases luminal pH and reduces affinity of uroguanylin and plecanatide for GC-C (but not guanylin, linaclotide, or STa). Taken together, the stimulation of GC-C results in water secretion and reduced enteric nociception.

Table 2 GC-C agonist clinical trial data for chronic idiopathic constipation

Drug	Study design	Demographics/study size	Efficacy	Adverse effects
Linaclotide	2 randomized, 12-week, multicenter, double-blind, placebo-controlled, dual-dose trials Once daily linaclotide 145 μg, 290 μg, or placebo pill Administered 30 min prior to breakfast	Mean age: 48 years Gender: 89% female Race: 76% white Placebo: n=424 145 μg: n=430 290 μg: n=418	Primary endpoint responders: 145 μg: 16.0% 290 μg: 21.3% Placebo: 6.0%	Most common AE was diarrhea: 145 μg: 16.0% 290 μg: 14.2% Placebo: 4.7% Discontinuation due to diarrhea: 145 μg: 4.7% 290 μg: 3.8% Placebo: 0.5%
Plecanatide	Randomized, 12-week, multicenter, double-blind, placebo-controlled, dual-dose trial Once daily plecanatide 3 mg, 6 mg, or placebo pill Instructed to take with or without food	Mean age: 45 years Gender: 80% female Race: 70% white Placebo: n=454 3 mg: n=453 6 mg: n=441	Primary endpoint responders: 3 mg: 21.0% 6 mg: 19.5% Placebo: 10.2%	Most common AE was diarrhea: 3 mg: 5.9% 6 mg: 5.7% Placebo: 1.3% Discontinuation due to diarrhea: 3mg: 2.7% 6 mg: 2.6% Placebo: 0.4%

Abbreviations: GC-C, guanylyl cyclase C; AE, adverse event.