Prucalopride improves bowel function and colonic transit time in patients with chronic constipation: an integrated analysis.

OBJECTIVES: Constipation is often characterized by slow colonic transit, but the relationship between colonic transit time (CTT) and symptoms is unclear. The aims of this study were to investigate the effect of prucalopride, a 5-hydroxytryptamine receptor-4 agonist, on CTT and assess the relationship between CTT and symptoms. METHODS: This was an integrated analysis of three randomized, placebo-controlled, phase 2 dose-finding trials of prucalopride in patients with chronic constipation (ClinicalTrials.gov identifiers: NCT00617513; NCT00631813; and NCT00596596). Measurements of CTT were analyzed using radio-opaque markers at the start and end (4 or 12 weeks) of treatment. At these visits, patients assessed the presence and severity of their symptoms. RESULTS: In total, 280 patients had CTT measurements before and at the end of treatment and were included in the analysis. Their mean age was 43 years, 93% were women, and mean duration of constipation was 19 years. After a once daily treatment with prucalopride 2 mg (n=98) and 4 mg (n=70), CTT was reduced by 12.0 h (95% confidence interval (CI): -18.9, -5.1) and 13.9 h (95% CI: -20.5, -7.4), respectively; CTT increased by 0.5 h (95% CI: -4.5, 5.5) with placebo (n=112). At the end of the trial, symptoms including bloating/flatulence/distension and straining were rated as severe or very severe by a higher proportion of patients with slow or very slow CTT (>48 h) than by those with normal CTT. CONCLUSIONS: There was a clear relationship between increased CTT and increased symptom severity in patients with chronic constipation. Treatment with prucalopride accelerated CTT in these individuals.

Oral prucalopride in children with functional constipation.

BACKGROUND AND OBJECTIVES: Prucalopride is a selective, high-affinity 5-HT4 receptor agonist with gastrointestinal prokinetic activities. The aim of this study was to evaluate the pharmacokinetics, efficacy, safety, and tolerability of prucalopride oral solution in children, ages 4 years or older to 12 years or younger, with functional constipation. METHODS: A single oral dose of 0.03 mg/kg prucalopride was administered to 38 children to characterize prucalopride pharmacokinetics (NCT01674166). Thereafter, 37 children entered an open-label extension period in which 0.01 to 0.03 mg/kg of prucalopride was administered once per day for 8 weeks to investigate efficacy, safety, and tolerability (NCT01670669). RESULTS: Mean (standard deviation [SD]) Cmax, tmax, and AUC∞ (area under the plasma concentration-time curve from time 0 to infinity) were 3.8 (0.6) ng/mL, 1.8 (0.9) hour, and 65.3 (10.6) ng · h · mL, respectively, with limited (16%) variability in Cmax and AUC∞. Mean (SD) t1/2 was 19.0 (3.1) hours. On average, mean (SD) renal clearance (0.25 [0.08] L · h · kg) accounted for 54% of the apparent total plasma clearance (0.46 [0.07] L · h · kg). The apparent volume of distribution was 12.6 (2.6) L/kg. Prucalopride treatment resulted in a mean bowel movement frequency of 6.8/week, normal stool consistency, and reduced frequency of fecal incontinence. During the 8-week extension, 70% of study participants had at least 1 adverse event (all but 1 of mild/moderate intensity, 19% considered related to prucalopride). No children discontinued prucalopride because of adverse events. CONCLUSIONS: The pharmacokinetic profile of a single dose of prucalopride oral solution (0.03 mg · kg · day) generally resembled the profile in adults (2-mg tablet) but reflected lower systemic exposure in children. Prucalopride treatment for 8 weeks demonstrated an apparent favorable efficacy and tolerability profile in children with functional constipation.

Assessment of the cardiac safety of prucalopride in healthy volunteers: a randomized, double-blind, placebo- and positive-controlled thorough QT study.

AIMS: To assess steady-state effects of therapeutic and supra-therapeutic doses of prucalopride on the QT interval using a novel design involving a parallel placebo group with nested crossover for positive control. METHODS: A double-blind, double-dummy, placebo- and active-controlled study was conducted in 120 healthy male and female volunteers (NCT00903747). Volunteers were randomized to receive prucalopride 2-10 mg once daily (therapeutic and supratherapeutic doses, respectively) (group 1), placebo with 400 mg moxifloxacin on day 1 (group 2a), or placebo with moxifloxacin on day 15 (group 2b). Twelve-lead 24 h Holter ECGs recorded at various time-points were evaluated blind and centrally. RESULTS: Estimated mean difference in study specific corrected QT interval (QT(c)SS) time-matched change from baseline between prucalopride (2 and 10 mg) and placebo was <5 ms at all time points (maximum mean difference: 3.83 ms at 3.5 h post dose on day 5 with 2 mg [90% Cl -0.33, 6.38 ms]). Upper limits of the two-sided 90% CI for QT(c)SS were all <10 ms. There were no outlying QT(c)SS values >450 ms and no subjects had an increase >60 ms following prucalopride. Moxifloxacin produced the expected significant changes in QT(c)SS (>5 ms, maximum of +12.7 ms at 5 h post dose) at all time-points except 1 h post dose. Prucalopride resulted in small increases in heart rate (maximum of 5.8 beats min(-1)), which were similar for 2 and 10 mg. Prucalopride was well tolerated after first day of treatment. CONCLUSION: Prucalopride at both therapeutic and supra therapeutic doses has no clinically significant effects on cardiac repolarisation in healthy volunteers.

A placebo-controlled trial of prucalopride for severe chronic constipation.

BACKGROUND: In this 12-week trial, we aimed to determine the efficacy of prucalopride, a selective, high-affinity 5-hydroxytryptamine4 receptor agonist, in patients with severe chronic constipation. METHODS: In our multicenter, randomized, placebo-controlled, parallel-group, phase 3 trial, patients with severe chronic constipation (< or =2 spontaneous, complete bowel movements per week) received placebo or 2 or 4 mg of prucalopride, once daily, for 12 weeks. The primary efficacy end point was the proportion of patients having three or more spontaneous, complete bowel movements per week, averaged over 12 weeks. Secondary efficacy end points were derived from daily diaries and validated questionnaires completed by patients. Adverse events, clinical laboratory values, and cardiovascular effects were monitored. RESULTS: Efficacy was analyzed in 620 patients. The proportion of patients with three or more spontaneous, complete bowel movements per week was 30.9% of those receiving 2 mg of prucalopride and 28.4% of those receiving 4 mg of prucalopride, as compared with 12.0% in the placebo group (P<0.001 for both comparisons). Over 12 weeks, 47.3% of patients receiving 2 mg of prucalopride and 46.6% of those receiving 4 mg of prucalopride had an increase in the number of spontaneous, complete bowel movements of one or more per week, on average, as compared with 25.8% in the placebo group (P<0.001 for both comparisons). All other secondary efficacy end points, including patients' satisfaction with their bowel function and treatment and their perception of the severity of their constipation symptoms, were significantly improved with the use of 2 or 4 mg of prucalopride as compared with placebo, at week 12. The most frequent treatment-related adverse events were headache and abdominal pain. There were no significant cardiovascular effects of treatment. CONCLUSIONS: Over 12 weeks, prucalopride significantly improved bowel function and reduced the severity of symptoms in patients with severe chronic constipation. Larger and longer trials are required to further assess the risks and benefits of the use of prucalopride for chronic constipation. (ClinicalTrials.gov number, NCT00483886 [ClinicalTrials.gov].).

Efficacy and safety of oral prucalopride in women with chronic constipation in whom laxatives have failed: an integrated analysis.

BACKGROUND: Prucalopride is a selective, high-affinity, 5-hydroxytryptamine (serotonin) type 4 (5-HT4) receptor agonist with gastrointestinal prokinetic activities. This integrated analysis of data from three double-blind phase III trials (ClinicalTrials.gov: NCT00488137, NCT00483886, NCT00485940) compared the efficacy and safety of prucalopride 2 mg once daily in women with chronic constipation [≤2 spontaneous complete bowel movements (SCBM) per week] in whom laxatives had failed to provide adequate relief with that in the all-patient (AP) population of men and women with chronic constipation who had or had not obtained relief from laxatives. METHODS: Patients received prucalopride 2 mg or placebo once-daily for 12 weeks. Efficacy endpoints included an average of ≥3 SCBM/week and average increases of ≥1 SCBM/week and ≥1 SBM/week over this period. A response on any of these three endpoints was considered to be clinically relevant, and an overall response rate was derived for patients satisfying any of these endpoints. RESULTS: Of the AP population (n = 1318), 936 were women in whom laxatives had failed to provide adequate relief (WLF). More patients on prucalopride 2 mg than placebo had an average of ≥3 SCBM/week (AP 24.4 vs 11.0%; WLF 24.7 vs 9.2%), an average increase of ≥1 SCBM/week (AP 43.5 vs 24.8%; WLF 44.2 vs 22.6%), and an average increase of ≥1 SBM/week (AP 66.7 vs 38.4%; WLF 68.3 vs 37.0%) (all p < 0.001). Significant differences from placebo were evident in week 1 and sustained thereafter. Overall response rates in the AP and WLF populations, respectively, were 69.7 and 71.0% with prucalopride 2 mg and 44.5 and 41.6% with placebo (p < 0.001). Early (weeks 1-4) response predicted ultimate response over time. Common (>10%) adverse events were abdominal pain, nausea, diarrhoea, and headache. CONCLUSIONS: Prucalopride 2 mg once daily is effective in WLF. The efficacy and safety profile observed in WLF was similar to that in the total evaluated population of patients with chronic constipation who had or had not obtained adequate relief from laxatives.

Effect of prucalopride on the pharmacokinetics of oral contraceptives in healthy women.

BACKGROUND: Prucalopride is a selective, high-affinity, 5-hydroxytryptamine 4 (5-HT4) receptor agonist, which is approved for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. Women of childbearing potential, many of whom will be using oral contraceptives, comprise a large proportion of patients seeking medical therapy for constipation. OBJECTIVE: The aim of this study was to evaluate the effect of prucalopride on the absorption and steady-state pharmacokinetics of oral contraceptives in healthy women. METHODS: Sixteen women (aged 18-45 years) were enrolled in this open-label, two-way crossover trial (ClinicalTrials.gov identifier: NCT01036893) and given two 5-day treatments with a once-daily oral contraceptive (ethinylestradiol 0.035 mg + norethisterone 1 mg), alone and in combination with prucalopride 2 mg once daily. Treatments were separated by a 7 ± 2-day washout period. On days 1 and 5, blood samples were obtained pre-dose and at regular intervals post-dose up to 24 and 48 hours, respectively, to determine ethinylestradiol and norethisterone plasma concentrations. Prucalopride plasma concentrations were determined pre-dose and 3 hours post-dose on days 1 and 5, and 24 hours post-dose on day 6. Safety was assessed. RESULTS: Thirteen participants completed the study. One participant was thought to be non-compliant on days 3 and/or 4, and was excluded from the day 5 analysis. On days 1 and 5, maximum plasma concentrations of both oral contraceptive constituents were attained in ~1 hour and were unaffected by prucalopride administration. On day 5, steady-state prucalopride and oral contraceptive concentrations had been achieved. Prucalopride did not affect the pharmacokinetics of the oral contraceptives: point estimates for the maximum plasma concentration and area under the plasma concentration-time curve values and their associated 90 % confidence intervals were contained within predefined equivalence limits (80-125 %). Prucalopride was well tolerated, with a safety profile consistent with those observed in previous studies. CONCLUSION: Co-administration of prucalopride with an oral contraceptive did not result in any clinically meaningful pharmacokinetic interactions and was well tolerated.

Factors affecting satisfaction with treatment in European women with chronic constipation: An internet survey.

BACKGROUND: Data on factors affecting treatment satisfaction in European women with chronic constipation are limited. OBJECTIVE: To assess factors associated with treatment satisfaction among European women with chronic constipation. METHODS: A 2011-2012 internet survey was conducted in men and women from 12 European countries. Respondents analysed were female with self-reported chronic constipation (≥1 symptoms for ≥6 months of lumpy/hard stools, feeling of incomplete evacuation, and pain during defecation, as well as <3 bowel movements/week). For laxative users, satisfaction with treatment, factors affecting satisfaction, and interactions with healthcare professionals were collected. RESULTS AND CONCLUSIONS: In total, 4805/50,319 participants fulfilled the inclusion criteria (female with chronic constipation). Of the laxative users (1575/4805), 57% (n = 896) were satisfied with their treatment, while 26% were neutral, and 17% dissatisfied. Dissatisfied respondents visited their GP less frequently in the past 12 months, were more likely to obtain over-the-counter laxatives, and took a dose higher than recommended more frequently than those satisfied. Respondents were most satisfied with ease of use of treatment and least satisfied with relief from bloating. Newer treatments aimed at alleviating symptoms, particularly bloating, are required for respondents neutral or dissatisfied with their current treatment.

Effect of renal impairment on the pharmacokinetics of prucalopride: a single- dose open-label Phase I study.

OBJECTIVE: To evaluate the pharmacokinetics of prucalopride in individuals with renal impairment (RI). METHODS: This open-label Phase I study (ClinicalTrials.gov identifier: NCT01674192) enrolled men and women aged 18-75 years who were classified by renal function: normal renal function (creatinine clearance ≥ 80 mL/min/1.73 m²), mild RI (50-79 mL/min/1.73 m²), moderate RI (25-49 mL/min/1.73 m²), and severe RI (≤ 24 mL/min/1.73 m²). All received a single oral dose of prucalopride 2 mg. RESULTS: Thirty-four individuals (normal renal function: 10; mild RI: 8; moderate RI: 7; severe RI: 9) received prucalopride. In all groups, maximum plasma concentration was reached within 2-4 hours. There was no significant difference in exposure (area under the plasma concentration-time curve from time zero to infinity) between participants with mild RI and those with normal renal function. However, area under the plasma concentration-time curve from time zero to infinity values were 1.5- and 2.3-fold higher (P = 0.002 and P < 0.001) in patients with moderate RI and severe RI, respectively, than in those with normal renal function. The proportion of total body clearance accounted for by renal clearance was significantly reduced in those with RI. CONCLUSION: Clinically meaningful reductions in renal clearance were seen in participants with severe RI, which supports a decrease from the standard dose of prucalopride 2 mg daily to 1 mg daily in these individuals.