title: Plecanatide, an oral guanylate cyclase C agonist acting locally in the gastrointestinal tract, is safe and well-tolerated in single doses.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Synergy Pharmaceuticals, Inc., 3805 Old Easton Road, Doylestown, PA 18902, USA. shailu@synergypharma.com
authors.forename: Kunwar
authors.initials: K
authors.lastname: Shailubhai
authors.forename: Stephen
authors.initials: S
authors.lastname: Comiskey
authors.forename: John A
authors.initials: JA
authors.lastname: Foss
authors.forename: Rong
authors.initials: R
authors.lastname: Feng
authors.forename: Laura
authors.initials: L
authors.lastname: Barrow
authors.forename: Gail M
authors.initials: GM
authors.lastname: Comer
authors.forename: Gary S
authors.initials: GS
authors.lastname: Jacob
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D003109:Colonic Diseases, Functional / Q000188:drug therapy*; D003672:Defecation / Q000187:drug effects*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D045265:Natriuretic Peptides / Q000009:adverse effects* / Q000493:pharmacokinetics; D017461:Receptors, Atrial Natriuretic Factor / Q000819:agonists*; D055815:Young Adult
chemical_list: D045265:Natriuretic Peptides; C584575:plecanatide; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C