Original Article

Digestive Diseases and Sciences

, Volume 58, Issue 9, pp 2580-2586

First online:

Plecanatide, an Oral Guanylate Cyclase C Agonist Acting Locally in the Gastrointestinal Tract, Is Safe and Well-Tolerated in Single Doses

  • Kunwar ShailubhaiAffiliated withSynergy Pharmaceuticals, Inc. Email author 
  • , Stephen ComiskeyAffiliated withSynergy Pharmaceuticals, Inc.
  • , John A. FossAffiliated withSynergy Pharmaceuticals, Inc.
  • , Rong FengAffiliated withSynergy Pharmaceuticals, Inc.
  • , Laura BarrowAffiliated withSynergy Pharmaceuticals, Inc.
  • , Gail M. ComerAffiliated withSynergy Pharmaceuticals, Inc.
  • , Gary S. JacobAffiliated withSynergy Pharmaceuticals, Inc.

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Plecanatide, an analogue of uroguanylin, activates the guanylate cyclase C (GC-C) receptor found on the GI mucosal epithelial cells, leading to secretion of fluid, facilitating bowel movements. Plecanatide is being investigated as a potential treatment for constipating GI disorders. The aim of this investigation was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single doses of plecanatide in healthy volunteers.


A total of 72 healthy volunteers at a single site were randomized in 9 cohorts to receive oral plecanatide or placebo from 0.1 to 48.6 mg. Plasma PK samples were collected pre-dose and post-dose. PD assessments included time to first stool, stool frequency, and stool consistency using the Bristol Stool Form Scale. All adverse events were documented.


Plecanatide was safe and well-tolerated at all dose levels. A total of 17 of 71 subjects (23.9 %) reported 25 treatment-emergent adverse events (TEAEs) during the study. The number of TEAEs reported by subjects who received plecanatide or placebo was comparable (24.5 vs. 22.2 %, respectively). There were no dose-related increases in TEAEs or any SAEs reported. No measurable systemic absorption of oral plecanatide was observed at any of the oral doses studied, utilizing an assay sensitive down to 1 ng/mL.


Plecanatide, an oral GC-C agonist, acting locally within the GI tract without measurable systemic exposure, was safe and well-tolerated in single doses up to 48.6 mg. The study was not powered for statistical analyses, but trends in PD parameters supported continued clinical development.


Guanylate cyclase C (GC-C) Cystic fibrosis transmembrane conductance regulator (CFTR) Gastrointestinal (GI) Uroguanylin (UG) Cyclic GMP (cGMP) Chronic functional constipation (CC) Irritable bowel syndrome-constipation predominant (IBS-C)