MANAGEMENT OF CHRONIC CONSTIPATION BEYOND LAXATIVES

Enrique Rey Professor of Medicine Head. Department of Digestive Diseases Hospital Clínico San Carlos Complutense University Madrid, Spain MANAGEMENT OF CHRONIC CONSTIPATION BEYOND LAXATIVES

CONSTIPATION: MANAGEMENT Self-reported Constipation Chronic Constipation Lifestyle changes 25-30 g fiber intake daily 1.5-2 liters of liquid intake daily Daily physical exercise (1 hour) Laxatives PEG 3350 17 g/day SPS 10 mg/day 4-6 weeks Non controlled Constipation (refractory)

NEW HORIZONS

SEROTONINE AND MOTILITY

SEROTONINE AND GI TRACT Sanger GJ. Neurogastroenterol Mot 1996; 8:319-331 Gershon MD. Aliment Pharmacol Ther 1999; 13 (Suppl 2): 15-30 De Ponti. Gut 2004;53:1520 1535 Tonini. Dig Dis Sci 2006; 24: 59

SEROTONINA Y TUBO DIGESTIVO Sanger GJ. Neurogastroenterol Mot 1996; 8:319-331 Gershon MD. Aliment Pharmacol Ther 1999; 13 (Suppl 2): 15-30 De Ponti. Gut 2004;53:1520 1535 Tonini. Dig Dis Sci 2006; 24: 59

5HT4 RECEPTORS De Ponti. Gut 2004;53:1520 1535

5-HT4 AGONISTS

5-HT4 AGONISTS Drug 5-HT4 receptor 5HT3 receptor Other receptors Metoclopramide Agonist Antagonist D 2 Antagonist Cisapride Agonist Antagonist Channel herg Inhibitor Renzapride Agonist Antagonist Channel herg Inhibitor Tegaserod Prucalopride Agonist Agonist 5-HT 1 Agonist 5-HT 2 Antagonista

AFFINITY FOR KEY RECEPTORS 5-HT4 herg 5-HT1D y 2B Cardiovascular side effects Cisapride Tegaserod herg gen related K+ Channel 5HT-1D and 5-HT- 2B De Maeyer et al. Neurogastroenterol Motil 2008; 20:99 112

PRUCALOPRIDE: PHARMACOKINETICS Low binding to plasmatic proteins (28-33%) 4% No interaction with cytochrome P450 (CYP 3A4) Oral availability: 90% Not interfere by food 96% After a single dose of 2 mg: C max 7.5 ng/ml in 2-3 hours t ½ 30 h

PRUCALOPRIDE: PHYSIOLOGICAL EFFECTS

5-HT4 AGONISM : EFFECTS ON COLONIC MUSCULAR FIBERS Prins et al. Br J Pharmacol 2000 Celleck et al. Neurogastro Motil 2006; 18:853-61

Tiempo de transito colónico (h) PRUCALOPRIDE: EFFECT ON COLONIC MOTILITY (HEALTHY SUBJECTS) 45 40 35 30 Placebo PRU 2 mg 25 20 * 15 10 5 * * 0 Total Right Colon Left Colon Rectosigmoid Schryver et al. Aliment Pharmacol Ther 2002; 16: 603-612 Poen et al. Aliment Pharmacol Ther 1999; 13: 1493-1497

T ½ (hours) PRUCALOPRIDE: EFFECTS ON TRANSIT (CONSTIPATION) 250 200 Placebo PRU 2 mg PRU 4 mg 14 12 10 Placebo PRU 2 mg PRU 4 mg 150 100 * * 8 6 * 4 50 2 0 Gastric emptying Small (min) Bowel transit time(min) 0 Right colon emptying Bouras et al. Gastroenterology 2001;120:354-360

PRUCALOPRIDE: MAIN CHARACTERISTICS High selective 5-HT 4 receptor agonist Excellent oral bioavailability, long half life, and renal excretion One daily dose Acts on enteric nervous system Stimulates colonic motility Increases high amplitude contractions Acelerates colonic transit

PRUCALOPRIDE: EFFICACY

OUR PATIENT WITH CONSTIPATION

PRUCALOPRIDE: DEVELOPMENT PROGRAM Phase Number of studies Number of participants exposed (PRU) Phase I 48 797 Phase II DBPC trial (Chronic constipation) 10 Phase III DBPC trial (Chronic constipation) 6 2.717 Phase II/III follow up (open trial) 6 2.595 Phase II Postoperative ileo 2 283 Pase II Multiple sclerosis/ spinal injury with Crhonic constipation 7 386 TOTAL 83 >3.000 pacientes (PRU)

MAIN DBPC TRIALS USA-11 N = 620 (88% women) Multicenter USA (38 centers) Camilleri et al. N Engl J Med 2008; 358: 2344 INT-6 N = 716 (91% women) Multicenter international (65 centers; Europe, Australia, Canada y Southafrica) Tack et al. Gut 2009; 58: 357 USA-13 N = 641 (87% women) Multicenter USA (41 center) Quigley et al. Aliment Pharmacol Ther 2009; 29: 315

DESIGN Placebo, od Prucalopride 2 mg, od Prucalopride 4 mg, od Open run-in (2 wk) Doble blind period of intervention 0 2 4 8 12 Screening Rescue: Bisacodile (up to 15 mg) when no bowel movements in 3 days Randomization Endpoint Camilleri et al. N Engl J Med 2008; 358: 2344 Tack et al. Gut 2009; 58: 357; Quigley et al. Aliment Pharmacol Ther 2009; 29: 315

INCLUSION CRITERIA AND ENDPOINTS 18 y-o Chronic constipation, defined as: 2 spontaneous and complete BM weekly for at least 6 months 1 of the following criteria in at least 25% of BM: Hard or very hard stools Feeling of incomplete evacuation Straining Primary Endpoint Proportion of patients with a weekly mean of 3 spontaneous and complete evacuations for 12 weeks Secondary Endpoints Proportion of patients with least an increased of weekly mean of spontaneous and complete evacuations for 12 weeks Changes in constipation related symptoms (PAC-SYM) Changes in constipation related quality of life (PAC-QOL)

CHARACTERISTICS OF INCLUDED PATIENTS Variable Placebo (N = 645) Prucalopride 2 mg (N = 640) Prucalopride 4 mg (N = 639) Constipation Duration (years) 20.4 19.8 20.2 Number of weekly spontaneous evacuations (%) None 40.2 39.2 41.0 One 34.7 35.0 32.2 Previous laxative use (%) 86.2 85.6 84.7 Reported Efficacy of laxatives Failure 83.0 81.5 83.8 Camilleri et al. N Engl J Med 2008; 358: 2344 Tack et al. Gut 2009; 58: 357; Quigley et al. Aliment Pharmacol Ther 2009; 29: 315

PRIMARY ENDPOINT: % RESPONDERS Placebo Prucalopride 2 mg Prucaloprida 4 mg 11,3% 23,6% * 24,7% * 9,6% 19,5% * 23,6% 23,9% 23,5% * * * 12,1% 12,0% 30,9% * 28,4% * n=645 n=640 n=639 n=240 n=236 n=237 n=207 n=209 n=204 n=209 n=207 n=204 Grouped Tack, 2009 Camilleri, 2008 Quigley, 2009 * p<0,01 Camilleri et al. N Engl J Med 2008; 358: 2344 Tack et al. Gut 2009; 58: 357; Quigley et al. Aliment Pharmacol Ther 2009; 29: 315

SECONDARY ENDPOINT: SYMPTOMS (PAC-SYM) Bloating Discomfort Pain Cramps Incomplete Evacuation Tenesm Straining Stools too hard Stools too loose Painful defecation Anal burning sensation Anal bleeding 0.0 0.2 0.5 0.8 1.0 Placebo (n=538) Improvement PRU 2 mg (n=521) Kerstens et al. UEGW 2010

SECONDARY ENDPOINT: QUALITY OF LIFE Placebo Prucalopride 2 mg Prucaloprida 4 mg 22,2% 44,0% 43,3% * * 16,4% 33,5% * 29,4% * 26,0% 43,5% 44,4% * * 24,1% 44,9% * 48,7% * n=645 n=640 n=639 n=240 n=236 n=237 n=207 n=209 n=204 n=209 n=207 n=204 Grouped Tack, 2009 Camilleri, 2008 Quigley, 2009 Patients with an increase of at least one point in PAC-QOL at week 12 12 (%) * p<0,01 Camilleri et al. N Engl J Med 2008; 358: 2344 Tack et al. Gut 2009; 58: 357; Quigley et al. Aliment Pharmacol Ther 2009; 29: 315

% respondedores OVERALL CLINICAL BENEFIT 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 3 SCBM Δ 1 SCBM Δ 1 Satisf Δ 1 SBM Modificado de Stanghellini et al. UEGW 2010

PRUCALOPRIDE: SAFETY

% of patients % de pacientes ADVERSE EVENTS 30% 25% 30% 25% 20% 15% 10% 5% 20% 15% 10% 5% 0% Headache Nausea Diarrhea Abdominal pain 0% Headache Nausea Diarrhea Abdominal pain Placebo PRU 2 mg PRU 4 mg Placebo PRU 2 mg PRU 4 mg Tack et al. DDW 2008

QT INTERVAL QT Interval Placebo Prucalopride 2 mg Prucalopride 4 mg QTcB n=583* n=574* n=580* 450 480 ms (%) 5.7 5.7 8.4 480 500 ms (%) 0.5 0.7 1.0 >500 ms (%) 0.3 0.5 0.2 QTcF n=621* n=604* n=601* 450 480 ms (%) 3.5 2.5 3.5 480 500 ms (%) 0 0.5 0 >500 ms (%) 0 0 0.2 *Number of patients with QT interval within normal range at screening QTcB: intervalo QT corregido con la fórmula de Bazett QTcF: intervalo QT corregido con la fórmula de Fridericia Tack et al. DDW 2008

SAFETY IN THE ELDERLY Population: Chronic constipation (N=89 patients) Setting: Nursing home (mean agea>80 años; over 70% under active treatment for cardiovascular diseases Intervention: DBPC: 3 doses of prucalipride (0.5, 1 and 2 mg) vs placebo No serious adverse events related to Prucalopride Camilleri et al. Neurogastroenterol Motil (2009) 21, 1256 e117

SAFETY IN THE ELDERLY No changes in heart rate or blood pressure ECG Holter: no increase in the number of ventricular extra beats or episodes of ventricular tachiarrithmias Camilleri et al. Neurogastroenterol Motil (2009) 21, 1256 e117

PORT-MARKETING EXPOSURE Prucalopride is approved in a total of 46 countries and is currently being marketed in 16 of those countries (Australia, Belgium, Canada, Cyprus, France, Germany, Spain, Greece, Aus tria, Switzerland, Malta, Sweden, Ireland, Italy, UK and Singapore). Shire Data on File SPD555-15

ALGORITMO MANEJO Tack et al. Neurogastro Motil 2011; 23:697-710