Prucalopride: A Review in Chronic Idiopathic Constipation
- 641 Downloads
- 5 Citations
Abstract
Prucalopride (Resolor®), a highly selective serotonin 5-HT4 receptor agonist, is indicated in the European Economic Area for the treatment of adults with chronic idiopathic constipation (CIC) in whom laxatives have failed to provide adequate relief. This article reviews the pharmacological properties of prucalopride and its clinical efficacy and tolerability in patients with CIC. In five well-designed, 12-week trials in patients with CIC, oral prucalopride 2 mg/day was significantly more effective than placebo at improving bowel function, including the number of bowel movements and a range of other constipation symptoms, as well as health-related quality of life and patient satisfaction; however, no significant differences in bowel function measures were observed between prucalopride and placebo in a 24-week trial. Oral PEG-3350 + electrolytes reconstituted powder was found to be noninferior but not superior to prucalopride according to primary endpoint data from a 4-week, controlled-environment trial. Prucalopride was generally well tolerated in clinical trials; the most common adverse events were headache, diarrhoea, nausea and abdominal pain. No cardiovascular safety issues have arisen with prucalopride treatment. Although further long-term and comparative data would be beneficial, prucalopride provides an additional treatment option for patients with CIC.
Keywords
Placebo Recipient Tegaserod hERG Channel Functional Constipation LubiprostoneNotes
Acknowledgments
During the peer review process, the manufacturer of prucalopride was also offered an opportunity to review this article. Any changes resulting from comments received were made on the basis of scientific and editorial merit.
Compliance with Ethical Standards
Funding
The preparation of this review was not supported by any external funding.
Conflict of interest
Karly Garnock-Jones is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.
References
- 1.Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology. 2006;130(5):1480–91.PubMedCrossRefGoogle Scholar
- 2.Ford AC, Moayyedi P, Lacy BE, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014;109(Suppl. 1):S2–26.PubMedCrossRefGoogle Scholar
- 3.Quigley EM. Prucalopride: safety, efficacy and potential applications. Ther Adv Gastroenterol. 2012;5(1):23–30.CrossRefGoogle Scholar
- 4.European Medicines Agency. Resolor® (prucalopride tablets): EU summary of product characteristics. 2015. http://www.ema.europa.eu/. Accessed 4 Nov 2015.
- 5.Shire. Shire receives European approval to use Resolor® (prucalopride) in men for the symptomatic treatment of chronic constipation [media release]. 3 June 2015. https://www.shire.com.
- 6.European Medicines Agency. Resolor (prucalopride) assessment report (procedure no. EMEA/H/C/001012/II/0034). 2015. http://www.ema.europa.eu. Accessed 4 Nov 2015.
- 7.Briejer MR, Bosmans JP, Van Daele P, et al. The in vitro pharmacological profile of prucalopride, a novel enterokinetic compound. Eur J Pharmacol. 2001;423(1):71–83.PubMedCrossRefGoogle Scholar
- 8.Keating GM. Prucalopride: a review of its use in the management of chronic constipation. Drugs. 2013;73(17):1935–50.PubMedCrossRefGoogle Scholar
- 9.Wong BS, Manabe N, Camilleri M. Role of prucalopride, a serotonin (5-HT(4)) receptor agonist, for the treatment of chronic constipation. Clin Exp Gastroenterol. 2010;3:49–56.PubMedPubMedCentralGoogle Scholar
- 10.Briejer MR, Prins NH, Schuurkes JA. Effects of the enterokinetic prucalopride (R093877) on colonic motility in fasted dogs. Neurogastroenterol Motil. 2001;13(5):465–72.PubMedCrossRefGoogle Scholar
- 11.Bouras EP, Camilleri M, Burton DD, et al. Prucalopride accelerates gastrointestinal and colonic transit in patients with constipation without a rectal evacuation disorder. Gastroenterology. 2001;120(2):354–60.PubMedCrossRefGoogle Scholar
- 12.Emmanuel AV, Roy AJ, Nicholls TJ, et al. Prucalopride, a systemic enterokinetic, for the treatment of constipation. Aliment Pharmacol Ther. 2002;16(7):1347–56.PubMedCrossRefGoogle Scholar
- 13.Cinca R, Chera D, Gruss HJ, et al. Randomised clinical trial: macrogol/PEG 3350 + electrolytes versus prucalopride in the treatment of chronic constipation—a comparison in a controlled environment. Aliment Pharmacol Ther. 2013;37(9):876–86.PubMedCrossRefGoogle Scholar
- 14.Emmanuel A, Cools M, Vandeplassche L, et al. Prucalopride improves bowel function and colonic transit time in patients with chronic constipation: an integrated analysis. Am J Gastroenterol. 2014;109(6):887–94.PubMedPubMedCentralCrossRefGoogle Scholar
- 15.Poen AC, Felt-Bersma RJ, Van Dongen PA, et al. Effect of prucalopride, a new enterokinetic agent, on gastrointestinal transit and anorectal function in healthy volunteers. Aliment Pharmacol Ther. 1999;13(11):1493–7.PubMedCrossRefGoogle Scholar
- 16.Bouras EP, Camilleri M, Burton DD, et al. Selective stimulation of colonic transit by the benzofuran 5HT4 agonist, prucalopride, in healthy humans. Gut. 1999;44(5):682–6.PubMedPubMedCentralCrossRefGoogle Scholar
- 17.Emmanuel AV, Kamm MA, Roy AJ, et al. Effect of a novel prokinetic drug, R093877, on gastrointestinal transit in healthy volunteers. Gut. 1998;42(4):511–6.PubMedPubMedCentralCrossRefGoogle Scholar
- 18.Sloots CE, Poen AC, Kerstens R, et al. Effects of prucalopride on colonic transit, anorectal function and bowel habits in patients with chronic constipation. Aliment Pharmacol Ther. 2002;16(4):759–67.PubMedCrossRefGoogle Scholar
- 19.Miner P, Camilleri M, Burton D, et al. Prucalopride induces high amplitude propagated contractions in the colon of patients with chronic constipation: a randomized study [abstract]. Neurogastroenterol Motil. 2015;27(Suppl. 2):86.Google Scholar
- 20.De Maeyer JH, Straetemans R, Schuurkes JA, et al. Porcine left atrial and sinoatrial 5-HT(4) receptor-induced responses: fading of the response and influence of development. Br J Pharmacol. 2006;147(2):140–57.PubMedPubMedCentralCrossRefGoogle Scholar
- 21.De Maeyer JH, Schuurkes JA, Lefebvre RA. Selective desensitization of the 5-HT4 receptor-mediated response in pig atrium but not in stomach. Br J Pharmacol. 2009;156(2):362–76.PubMedPubMedCentralCrossRefGoogle Scholar
- 22.Krobert KA, Brattelid T, Levy FO, et al. Prucalopride is a partial agonist through human and porcine atrial 5-HT4 receptors: comparison with recombinant human 5-HT4 splice variants. Naunyn Schmiedebergs Arch Pharmacol. 2005;371(6):473–9.PubMedCrossRefGoogle Scholar
- 23.Pau D, Workman AJ, Kane KA, et al. Electrophysiological effects of prucalopride, a novel enterokinetic agent, on isolated atrial myocytes from patients treated with beta-adrenoceptor antagonists. J Pharmacol Exp Ther. 2005;313(1):146–53.PubMedCrossRefGoogle Scholar
- 24.Chapman H, Pasternack M. The action of the novel gastrointestinal prokinetic prucalopride on the HERG K+ channel and the common T897 polymorph. Eur J Pharmacol. 2007;554(2–3):98–105.PubMedCrossRefGoogle Scholar
- 25.Potet F, Bouyssou T, Escande D, et al. Gastrointestinal prokinetic drugs have different affinity for the human cardiac human ether-a-gogo K(+) channel. J Pharmacol Exp Ther. 2001;299(3):1007–12.PubMedGoogle Scholar
- 26.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. 2012;35(7):745–67.PubMedPubMedCentralCrossRefGoogle Scholar
- 27.De Maeyer JH, Lefebvre RA, Schuurkes JA. 5-HT4 receptor agonists: similar but not the same. Neurogastroenterol Motil. 2008;20(2):99–112.PubMedCrossRefGoogle Scholar
- 28.Mendzelevski B, Ausma J, Chanter DO, et al. Assessment of the cardiac safety of prucalopride in healthy volunteers: a randomized, double-blind, placebo- and positive-controlled thorough QT study. Br J Clin Pharmacol. 2012;73(2):203–9.PubMedPubMedCentralCrossRefGoogle Scholar
- 29.Flach S, Troy S, Pankratz T, et al. A phase 1 study to investigate the absorption, metabolism and excretion of 14C prucalopride after a single oral dose [abstract no. P0979]. United Eur Gastroenterol J. 2014;2(1S):A401.Google Scholar
- 30.Smith WB, Mannaert E, Verhaeghe T, et al. Effect of renal impairment on the pharmacokinetics of prucalopride: a single-dose open-label phase I study. Drug Des Devel Ther. 2012;6:407–15.PubMedPubMedCentralGoogle Scholar
- 31.Van de Velde V, Vandeplassche L, van Dijck W, et al. Effects of moderate or severe hepatic impairment on the pharmacokinetics of prucalopride [abstract no. P0958]. Gut. 2012;61(Suppl. 3):A306.Google Scholar
- 32.Van de Velde V, Vandeplassche L, Hoppenbrouwers M, et al. Effect of prucalopride on the pharmacokinetics of oral contraceptives in healthy women. Drugs R D. 2013;13(1):43–51.PubMedPubMedCentralCrossRefGoogle Scholar
- 33.Yiannakou Y, Piessevaux H, Bouchoucha M, et al. A randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy, safety, and tolerability of prucalopride in men with chronic constipation. Am J Gastroenterol. 2015;110(5):741–8.PubMedPubMedCentralCrossRefGoogle Scholar
- 34.Tack J, van Outryve M, Beyens G, et al. Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives. Gut. 2009;58(3):357–65.PubMedCrossRefGoogle Scholar
- 35.Quigley EM, Vandeplassche L, Kerstens R, et al. Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation—a 12-week, randomized, double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2009;29(3):315–28.PubMedCrossRefGoogle Scholar
- 36.Camilleri M, Kerstens R, Rykx A, et al. A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med. 2008;358(22):2344–54.PubMedCrossRefGoogle Scholar
- 37.Muller-Lissner S, Rykx A, Kerstens R, et al. A double-blind, placebo-controlled study of prucalopride in elderly patients with chronic constipation. Neurogastroenterol Motil. 2010;22(9):991–8 (e255).Google Scholar
- 38.Piessevaux H, Corazziari E, Rey E, et al. A randomized, double-blind, placebo-controlled trial to evaluate the efficacy, safety, and tolerability of long-term treatment with prucalopride. Neurogastroenterol Motil. 2015;27(6):805–15.PubMedCrossRefGoogle Scholar
- 39.Ke M, Zou D, Yuan Y, et al. Prucalopride in the treatment of chronic constipation in patients from the Asia-Pacific region: a randomized, double-blind, placebo-controlled study. Neurogastroenterol Motil. 2012;24(11):999-e541.PubMedPubMedCentralCrossRefGoogle Scholar
- 40.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. 2010;32(9):1113–23.PubMedCrossRefGoogle Scholar
- 41.Piessevaux H, Camilleri M, Yiannakou Y, et al. Efficacy and safety of prucalopride in chronic constipation: an integrated analysis of six randomized controlled clinical trials [abstract no. Sa1390 plus poster]. Gastroenterology. 2015;148:S-311.Google Scholar
- 42.Ke M, Tack J, Quigley EMM, et al. Effect of prucalopride in the treatment of chronic constipation in Asian and non-Asian women: a pooled analysis of 4 randomized, placebo-controlled studies. J Neurogastroenterol Motil. 2014;20(4):458–68.PubMedPubMedCentralCrossRefGoogle Scholar
- 43.Gatta L, Kerstens R, Scarpignato C. How effective is prucalopride for the treatment of chronic constipation? A systematic review and meta-analysis [abstract no. Su2069]. Gastroenterology. 2013;144(5 Suppl. 1):S547-S8.Google Scholar
- 44.Shin A, Camilleri M, Kolar G, et al. Systematic review with meta-analysis: highly selective 5-HT4 agonists (prucalopride, velusetrag or naronapride) in chronic constipation. Aliment Pharmacol Ther. 2014;39(3):239–53.PubMedCrossRefGoogle Scholar
- 45.Tack J, Camilleri M, Dubois D, et al. Association between health-related quality of life and symptoms in patients with chronic constipation: an integrated analysis of three phase 3 trials of prucalopride. Neurogastroenterol Motil. 2015;27(3):397–405.PubMedCrossRefGoogle Scholar
- 46.Tack J, Stanghellini V, Dubois D, et al. Effect of prucalopride on symptoms of chronic constipation. Neurogastroenterol Motil. 2014;26(1):21–7.PubMedCrossRefGoogle Scholar
- 47.Tack J, Quigley E, Camilleri M, et al. Efficacy and safety of oral prucalopride in women with chronic constipation in whom laxatives have failed: an integrated analysis. United Eur Gastroenterol J. 2013;1(1):48–59.CrossRefGoogle Scholar
- 48.Leelakusolvong S, Ke M, Zou D, et al. Factors predictive of treatment-emergent adverse events of prucalopride: an integrated analysis of four randomized, double-blind, placebo-controlled trials. Gut Liver. 2015;9(2):208–13.PubMedPubMedCentralCrossRefGoogle Scholar
- 49.Gatta L, Scarpignato C. Cardiac safety of prucalopride in randomized clinical trials of patients with chronic constipation [abstract no. OC.05.4]. Dig Liver Dis. 2014;46(Suppl. 2):S14.CrossRefGoogle Scholar
- 50.Gatta L, Scarpignato C. How safe is prucalopride for the treatment of chronic constipation? A systematic review and meta-analysis [abstract no. ISP3844-47]. Drug Saf. 2013;36(9):937.Google Scholar
- 51.Tack J, Muller-Lissner S, Stanghellini V, et al. Diagnosis and treatment of chronic constipation—a European perspective. Neurogastroenterol Motil. 2011;23(8):697–710.PubMedPubMedCentralCrossRefGoogle Scholar
- 52.Dhruva Rao PK, Lewis M, Peiris SP, et al. Long term outcome of Prucalopride for chronic constipation: a single centre study. Colorectal Dis. 2015. doi: 10.1111/codi.12993.
- 53.Ford AC. Death knell for placebo-controlled trials in chronic idiopathic constipation? Gastroenterology. 2013;145(4):897–8.PubMedCrossRefGoogle Scholar
- 54.Nuijten M, Dubois D, Joseph A, et al. Cost-effectiveness of prucalopride in the treatment of chronic constipation in the Netherlands. Front Pharmacol. 2015. http://dx.doi.org/10.3389/fphar.2015.00067.
- 55.Walsh C, Murphy J, Quigley EM. Pharmacoeconomic study of chronic constipation in a secondary care centre. Ir J Med Sci. 2015;184(4):863–70.PubMedCrossRefGoogle Scholar
- 56.Winter HS, Di Lorenzo C, Benninga MA, et al. Oral prucalopride in children with functional constipation. J Pediatr Gastroenterol Nutr. 2013;57(2):197–203.PubMedCrossRefGoogle Scholar
- 57.Mugie SM, Korczowski B, Bodi P, et al. Prucalopride is no more effective than placebo for children with functional constipation. Gastroenterology. 2014;147(6):1285–95.e1.Google Scholar
- 58.Nurko S, Saps M. Treating constipation with prucalopride: one size does not fit all. Gastroenterology. 2014;147(6):1214–6.PubMedCrossRefGoogle Scholar