Use of prucalopride in adults with chronic idiopathic constipation

ABSTRACT

Introduction: Prucalopride is a selective 5-HT₄ receptor agonist with colonic prokinetic activity. It was recently approved by the FDA for the treatment of chronic idiopathic constipation. Before this approval, there were limited options to improve colonic motility in the treatment of chronic idiopathic constipation.

Areas covered: We systematically searched PubMed, Embase, ClinicalTrials.gov, and international conference presentations, and we reviewed all studies that evaluated prucalopride for the treatment of chronic idiopathic constipation in adults. In this review, we discuss the pharmacokinetics, pharmacodynamics, receptor interactions, phase I-IV clinical trials, and safety outcomes of prucalopride in adults, including the elderly.

Expert opinion: Prucalopride is an effective agent to improve colonic motility, decrease colonic transit time, and increase complete spontaneous bowel movements in patients with chronic idiopathic constipation. Unlike previously available 5-HT₄ receptor agonists such as cisapride and tegaserod, prucalopride does not interact with the cardiac hERG potassium channels or other serotonergic receptors in blood vessels and is not associated with an increase in major adverse cardiovascular events. Additionally, prucalopride has demonstrated promise in the treatment of gastroparesis, post-operative ileus, and opioid-induced constipation. Prucalopride directly stimulates colonic motility, differentiating it from all other medications (exclusively osmotic or chloride secretagogues) approved for chronic constipation in the last decade.

KEYWORDS:

• Serotonin
• prokinetic
• bowel function
• colonic transit time
• colonic motility

Article Highlights

• Prucalopride is a 5-HT₄ receptor agonist that activates longitudinal muscle contraction and results in high amplitude propagating contractions, resulting in decreased colonic transit.

• Prucalopride is available for patients with chronic idiopathic constipation at 2 mg and 1 mg for those with impaired renal clearance (glomerular filtration rate < 30 mL/min/1.73 m²); the 1 mg dose is approved in Europe for use in patients > 65 years of age.

• Though not approved for use in children or adolescents, there is some evidence of the efficacy of prucalopride in the treatment of constipation in this age group.

• Prucalopride does not have the same QTc prolonging effects as the previous 5-HT₄ receptor agonists (particularly cisapride).

• Future potential uses for prucalopride include gastroparesis, impaired esophageal motility, post-operative ileus, and visceral neuropathy and myopathy.

Declaration of interest

M Camilleri has conducted single center research studies with prucalopride (Janssen), and with TAK-954 and relamorelin, both unapproved medications, sponsored respectively by Takeda and Rhythm Pharmaceuticals, Boston. M Camilleri serves as advisor to Shire, Takeda and Allergan, with monetary remuneration to his employer, Mayo Clinic.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Information Resources for Further Reading

Camilleri M, Van Outryve MJ, Beyens G, et al. Clinical trial: the efficacy of open-label prucalopride treatment in patients with chronic constipation - follow-up of patients from the pivotal studies. Aliment Pharmacol Ther 32, 1113–23 (2010).

Camilleri M, Kerstens R, Rykx A, et al. A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med 358, 2344–54 (2008).

De Schryver AM, Andriesse GI, Samsom M, et al. The effects of the specific 5HT(4) receptor agonist, prucalopride, on colonic motility in healthy volunteers. Aliment Pharmacol Ther 16, 603–12 (2002).

Tack J, Camilleri M, Chang L, et al. Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders. Aliment Pharmacol Ther 35, 745–67 (2012).

Additional information

Funding

This paper was not funded.