Prucalopride (Resolor) is a selective, high-affinity 5HT4 agonist.1 It acts on 5HT4 receptors in the gut to accelerate colonic transit; higher doses also seem to enhance gastric emptying and small bowel transit.2
Prucalopride was evaluated in three pivotal trials of identical design, one conducted in Europe and two carried out in the US. Following a two-week run-in phase, investigators randomised males and females with chronic constipation to receive once daily 2mg or 4mg oral doses of prucalopride, or placebo, for 12 weeks. The primary end point in each study was the proportion of patients who experienced a response, defined as an average of three or more spontaneous, complete bowel movements per week.3-5
In the first trial (PRU-INT-6), the intention-to-treat population comprised 713 patients. The proportion of these individuals who experienced a response over the treatment period was significantly greater in the prucalopride 2mg and 4mg groups (19.5% and 23.6%, respectively) than in the placebo group (9.6%; p≤0.01 versus prucalopride 2mg and p≤0.001 versus prucalopride 4mg).3
The second trial (PRU-USA-11) enrolled 628 patients, of whom 620 were included in the intention-to-treat analysis. Compared with the placebo-treated patients, more than twice as many of the patients who received prucalopride responded to treatment (30.9% for the 2mg dose and 28.4% for the 4mg dose versus 12.0% for placebo; p<0.001 for both comparisons).4
A total of 651 patients were enrolled in the third trial (PRU-USA-13); 641 received study medication and qualified for the intention-to-treat analysis. Again, response rates in the prucalopride-treated patients (23.9% and 23.5% at the 2mg and 4mg doses, respectively) were greater than in the placebo-treated patients (12.1%; p≤0.01 for both comparisons).5
The key secondary end point in the pivotal studies was the proportion of patients who experienced an increase in spontaneous, complete bowel movements of at least one per week. In all the studies, this proportion was significantly greater for both prucalopride doses than for placebo (p≤0.001 or p<0.001 for all comparisons).2
Overall, prucalopride was associated with a consistent and significant improvement in patients' satisfaction with their treatment and bowel habits, as assessed by the Patient Assessment of Constipation Quality of Life questionnaire (PAC-QOL). The proportion of participants who had a ≥1-point improvement in the 5-point satisfaction subscale score of the PAC-QOL was 45.3% in those on prucalopride 2mg, compared with 21.3% in those who received placebo.2
Analysis of pooled safety data from the three studies indicated that prucalopride was generally well tolerated; in most cases, adverse effects were mild to moderate and transient. The most common prucalopride-related adverse events were headache, nausea, diarrhoea and abdominal pain. Unlike non-selective gastroprokinetic 5HT4 agonists, prucalopride does not seem to prolong QT interval.2
Although the three pivotal trials of prucalopride recruited both males and females, almost 90% of participants were female. As a result, concerns arose during regulatory assessment that the drug had not been sufficiently evaluated in men; therefore, approval was granted for use only in women. There is no evidence that prucalopride's pharmacokinetics, pharmacodynamics or mechanism of action differ between men and women, although men may require a higher dose. Movetis, the manufacturer of prucalopride, is expected to perform a post-authorisation efficacy study in men.2
Prucalopride is administered as a once daily 1mg or 2mg dose.1 In pivotal trials, the 4mg dose did not provide a significant incremental benefit over the 2mg dose.2
- Resolor Summary of Product Characteristics, 2009.
- CHMP Assessment Report for Resolor. EMEA/H/C/1012.
- Tack J et al. Gut 2009; 58: 357-65.
- Camilleri M et al. N Engl J Med 2008; 358: 2344-54.
- Quigley EM et al. Aliment Pharmacol Ther 2009; 29: 315-28.
Further information: Movetis