Plecanatide, an Oral Guanylate Cyclase C Agonist Acting Locally in the Gastrointestinal Tract, Is Safe and Well-Tolerated in Single Doses
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.
KeywordsGuanylate 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)
Authors are grateful to ClinPharm Consulting, LLC (Research Triangle Park, NC, USA) for their assistance in preparation of this manuscript. This study was funded by Synergy Pharmaceuticals.
Conflict of interest
All authors are employees of Synergy Pharmaceuticals, Inc.
- 5.Linzess (linaclotide) Full Prescribing Information. Available at: http://www.frx.com/pi/linzess_pi.pdf. Accessed January 11, 2013.
- 8.Harris MS, Daniels OT. Core aspects of clinical development and trials in chronic idiopathic constipation. In: Catto-Smith AG, ed. Constipation-causes, diagnosis and treatment. Rijeka: InTech; 2012:147–172.Google Scholar
- 15.Currie MG, Kurtz C, Mahajan-Miklos S, Busby RW, Fretzen A, Geis S. Effects of single dose administration of MD-1100 on safety, tolerability, exposure, and stool consistency in healthy subjects. Am J Gastroenterol. 2005;100:S328. (Abstract #894).Google Scholar