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Prucalopride

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Subject: 5-HT4 receptor, YM-31636, Cinitapride, Dazopride, Robalzotan
Collection: Amides, Benzofurans, Chloroarenes, Ethers, Janssen Pharmaceutica, Motility Stimulants, Organochlorides, Piperidines, Serotonin Receptor Agonists
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Prucalopride

Prucalopride
Systematic (IUPAC) name
4-Amino-5-chloro-N-[1-(3-methoxypropyl)piperidin-4-yl]-2,3-dihydro-1-benzofuran-7-carboxamide
Clinical data
Trade names Resolor, Resotran
AHFS/Drugs.com
Licence data EMA:
Pregnancy cat.
  • AU: B1
  • Not recommended
Legal status
Routes Oral
Identifiers
CAS number  YesY
ATC code A06
PubChem
IUPHAR ligand
ChemSpider
UNII  YesY
Chemical data
Formula C18H26ClN3O3 
Mol. mass 367.870 g/mol
 YesY   

Prucalopride (brand name Resolor, developed by Johnson & Johnson and licensed to Movetis) is a drug acting as a selective, high affinity 5-HT4 receptor agonist[1] which targets the impaired motility associated with chronic constipation, thus normalising bowel movements.[2][3][4][5][6][7] Prucalopride was approved for use in Europe in 2009[8] and in Canada (named Resotran) on December 7, 2011[9] but it has not been approved by the Food and Drug Administration for use in the United States. The drug has also been tested for the treatment of chronic intestinal pseudo-obstruction.[10][11]

Contents

  • Mechanism of action 1
  • Pharmacokinetics 2
  • Efficacy 3
  • Side effects 4
  • Prescribing information 5
  • Contraindications 6
  • References 7
  • External links 8

Mechanism of action

Prucalopride, a first in class dihydro-benzofuran-carboxamide, is a selective, high affinity serotonin (5-HT4) receptor agonist with enterokinetic activities.[12] Prucalopride alters colonic motility patterns via serotonin 5-HT4 receptor stimulation: it stimulates colonic mass movements, which provide the main propulsive force for defecation.

The observed effects are exerted via highly selective action on 5-HT4 receptors:[12] prucalopride has >150-fold higher affinity for 5-HT4 receptors than for other receptors.[1][13] Prucalopride differs from other 5-HT4 agonists such as tegaserod and cisapride, which at therapeutic concentrations also interact with other receptors (5-HT1B/D and the cardiac human ether-a-go-go K+ or hERG channel respectively) and this may account for the adverse cardiovascular events that have resulted in the restricted availability of these drugs.[13] Clinical trials evaluating the effect of prucalopride on QT interval and related adverse events have not demonstrated significant differences compared with placebo.[12]

Pharmacokinetics

Prucalopride is rapidly absorbed (Cmax attained 2–3 hours after single 2 mg oral dose) and is extensively distributed. Metabolism is not the major route of elimination. In vitro, human liver metabolism is very slow and only minor amounts of metabolites are found. A large fraction of the active substance is excreted unchanged (about 60% of the administered dose in urine and at least 6% in faeces). Renal excretion of unchanged prucalopride involves both passive filtration and active secretion. Plasma clearance averages 317 ml/min, terminal half-life is 24–30 hours,[14] and steady-state is reached within 3–4 days. On once daily treatment with 2 mg prucalopride, steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7 ng/ml, respectively.[12]

In vitro data indicate that prucalopride has a low interaction potential, and therapeutic concentrations of prucalopride are not expected to affect the CYP-mediated metabolism of co-medicated medicinal products.[12]

Efficacy

The primary measure of efficacy in the clinical trials is three or more spontaneous complete bowel movements per week; a secondary measure is an increase of at least one complete spontaneous bowel movement per week.[7][15][16] Further measures are improvements in PAC-QOL[17] (a quality of life measure) and PAC-SYM[18] (a range of stool, abdominal, and rectal symptoms associated with chronic constipation). Infrequent bowel movements, bloating, straining, abdominal pain, and defecation urge with inability to evacuate can be severe symptoms, significantly affecting quality of life.[19][20][21][22][23]

In three large clinical trials, 12 weeks of treatment with prucalopride 2 and 4 mg/day resulted in a significantly higher proportion of patients reaching the primary efficacy endpoint of an average of ≥3 spontaneous complete bowel movements than with placebo.[7][15][16] There was also significantly improved bowel habit and associated symptoms, patient satisfaction with bowel habit and treatment, and HR-QOL in patients with severe chronic constipation, including those who did not experience adequate relief with prior therapies (>80% of the trial participants).[7][15][16] The improvement in patient satisfaction with bowel habit and treatment was maintained during treatment for up to 24 months; prucalopride therapy was generally well tolerated.[24][25]

Side effects

Prucalopride has been given orally to ~2700 patients with chronic constipation in controlled clinical trials. The most frequently reported side effects are headache and gastrointestinal symptoms (abdominal pain, nausea or diarrhoea). Such reactions occur predominantly at the start of therapy and usually disappear within a few days with continued treatment.[12]

Prescribing information

In the EEA, prucalopride is approved for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. The recommended dosage in adults is 2 mg administered orally once daily; exceeding this dosage is not expected to increase efficacy. The recommended starting dose in elderly patients (>65 years) is 1 mg once daily; thereafter the dosage can be increased to 2 mg once daily, if needed.[12]

Contraindications

Prucalopride is contraindicated where there is hypersensitivity to the active substance or to any of the excipients, renal impairment requiring dialysis, intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract, such as Crohn's disease, and ulcerative colitis and toxic megacolon/megarectum.[12]

References

  1. ^ a b Briejer, M. R.; Bosmans, J. P.; Van Daele, P.; Jurzak, M.; Heylen, L.; Leysen, J. E.; Prins, N. H.; Schuurkes, J. A. (2001). "The in vitro pharmacological profile of prucalopride, a novel enterokinetic compound". European Journal of Pharmacology 423 (1): 71–83.  
  2. ^ ClinicalTrials.gov NCT00793247
  3. ^ Emmanuel, A. V.; Kamm, M. A.; Roy, A. J.; Kerstens, R.; Vandeplassche, L. (2012). "Randomised clinical trial: The efficacy of prucalopride in patients with chronic intestinal pseudo-obstruction - a double-blind, placebo-controlled, cross-over, multiple n = 1 study". Alimentary Pharmacology & Therapeutics 35 (1): 48–55.  
  4. ^ Smart, C. J.; Ramesh, A. N. (2011). "The successful treatment of acute refractory pseudo-obstruction with Prucalopride". Colorectal Disease: no.  
  5. ^ Bouras, E. P.; Camilleri, M.; Burton, D. D.; McKinzie, S. (1999). "Selective stimulation of colonic transit by the benzofuran 5HT4 agonist, prucalopride, in healthy humans". Gut 44 (5): 682–686.  
  6. ^ Bouras, E. P.; Camilleri, M.; Burton, D. D.; Thomforde, G.; McKinzie, S.; Zinsmeister, A. R. (2001). "Prucalopride accelerates gastrointestinal and colonic transit in patients with constipation without a rectal evacuation disorder". Gastroenterology 120 (2): 354–360.  
  7. ^ a b c d Tack, J.; Van Outryve, M.; Beyens, G.; Kerstens, R.; Vandeplassche, L. (2008). "Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives". Gut 58 (3): 357–365.  
  8. ^ European Medicines Agency -EPAR
  9. ^ Health Canada, Notice of Decision for Resotran
  10. ^ Briejer, M. R.; Prins, N. H.; Schuurkes, J. A. (2001). "Effects of the enterokinetic prucalopride (R093877) on colonic motility in fasted dogs". Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society 13 (5): 465–472.  
  11. ^ Oustamanolakis, P.; Tack, J. (2012). "Prucalopride for chronic intestinal pseudo-obstruction". Alimentary Pharmacology & Therapeutics 35 (3): 398–9.  
  12. ^ a b c d e f g h SmPC. Summary of product characteristics Resolor (prucalopride) October, 2009: 1-9.
  13. ^ a b De Maeyer, JH; Lefebvre, RA; Schuurkes, JA (Feb 2008). "5-HT(4) receptor agonists: similar but not the same". Neurogastroenterol Motil 20 (2): 99–112.  
  14. ^ Frampton, J. E. (2009). "Prucalopride". Drugs 69 (17): 2463–2476.  
  15. ^ a b c Camilleri, M.; Kerstens, R.; Rykx, A.; Vandeplassche, L. (2008). "A Placebo-Controlled Trial of Prucalopride for Severe Chronic Constipation". New England Journal of Medicine 358 (22): 2344–2354.  
  16. ^ a b c Quigley, E. M. M.; Vandeplassche, L.; Kerstens, R.; Ausma, J. (2009). "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". Alimentary Pharmacology & Therapeutics 29 (3): 315–328.  
  17. ^ Marquis, P.; De La Loge, C.; Dubois, D.; McDermott, A.; Chassany, O. (2005). "Development and validation of the Patient Assessment of Constipation Quality of Life questionnaire". Scandinavian Journal of Gastroenterology 40 (5): 540–551.  
  18. ^ Frank, L.; Kleinman, L.; Farup, C.; Taylor, L.; Miner Jr, P. (1999). "Psychometric validation of a constipation symptom assessment questionnaire". Scandinavian journal of gastroenterology 34 (9): 870–877.  
  19. ^ Johanson, JF; Kralstein, J (2007). "Chronic constipation: a survey of the patient perspective.". Alimentary pharmacology & therapeutics 25 (5): 599–608.  
  20. ^ Koch, A.; Voderholzer, W. A.; Klauser, A. G.; Müller-Lissner, S. (1997). "Symptoms in chronic constipation". Diseases of the colon and rectum 40 (8): 902–906.  
  21. ^ McCrea, G. L.; Miaskowski, C.; Stotts, N. A.; MacEra, L.; Paul, S. M.; Varma, M. G. (2009). "Gender differences in self-reported constipation characteristics, symptoms, and bowel and dietary habits among patients attending a specialty clinic for constipation". Gender Medicine 6 (1): 259–271.  
  22. ^ Pare, P.; Ferrazzi, S.; Thompson, W. G.; Irvine, E. J.; Rance, L. (2001). "An epidemiological survey of constipation in Canada: definitions, rates, demographics, and predictors of health care seeking". The American Journal of Gastroenterology 96 (11): 3130–3137.  
  23. ^ Wald, A.; Scarpignato, C.; Kamm, M. A.; Mueller-Lissner, S.; Helfrich, I.; Schuijt, C.; Bubeck, J.; Limoni, C.; Petrini, O. (2007). "The burden of constipation on quality of life: results of a multinational survey". Alimentary Pharmacology & Therapeutics 26 (2): 227–236.  
  24. ^ Camilleri, M; Beyens, G; Kerstens, R; Vandeplassche, L (2009). "Long-term follow-up of safety and satisfaction with bowel function in response to oral prucalopride in patients with chronic constipation [Abstract]". Gastroenterology 136 (Suppl 1): 160.  
  25. ^ Van Outryve, MJ; Beyens, G; Kerstens, R; Vandeplassche, L (2008). "Long-term follow-up study of oral prucalopride (Resolor) administered to patients with chronic constipation [Abstract T1400]". Gastroenterology 134 (4 (suppl 1)): A547.  

External links

  • Resolor (prucalopride)- Movetis
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