Prucalopride: safety,efficacy and potential applications

The clinical context

Motility in constipation and irritable bowel syndrome

While defecatory dysfunction is thought to be due to difficulties at the level of the pelvic floor and, thus, is not a colonic motor disorder per se, slow-transit constipation is presumed to reflect a primary disorder of colonic motility. In support of this presumption, these patients who, by definition, have slow colonic transit, have been shown to demonstrate a variety of motor abnormalities on manometric studies of the colon. Foremost among these and the colonic function that has been most widely adopted for use in clinical trials, is slow transit through the entire colon or segments of the colon.

In clinical practice, colon transit is most usually measured using the radio-opaque marker technique [Lin et al. 2005]. This approach has been shown to provide an accurate and reproducible assessment of overall colonic transit and by examining the distribution of retained markers may give some hints as to whether the underlying problem is colonic inertia or defaecatory dysfunction. To plan appropriate treatment strategies, however, further testing may be required.

More accurate and dynamic assessments of colon transit, including the determination of transit within various segments of the colon can be obtained from radio-isotopic approaches. Though these methodologies have been largely confined to a few centers, they have been widely used in the initial assessment of potentially colo-kinetic drugs in clinical research protocols [Odunsi and Camilleri, 2009; von der Ohe and Camilleri, 1992].

More direct assessments of colonic motor function can be obtained by manometry. However, colonic manometry presents formidable challenges, foremost among these being that of positioning the catheter assembly in the first place and ensuring that it retains its position throughout the period of study. Furthermore, patterns of colonic motility are poorly defined and subject to tremendous variation between normal people, not to mention disease states. While the absence of the most recognizable pressure wave pattern, the high amplitude power contraction (HAPC), during a recording period of adequate duration, or following exposure to adequate stimulation, has been proposed as being of diagnostic value among children and both a reduced frequency and amplitude of HAPCs and an impaired colonic motor response to food and exercise have been reported among adults with CC, there is at present no consensus with regard to the utility of colonic manometry in clinical practice in the adult patient [Camilleri et al 2008a, 1998] and the role of this modality in drug development has been limited.

Conditions such as CC and IBS, whose definitions rest exclusively on the interpretation of symptoms, are likely to encompass a heterogeneous population whose constituents may ultimately be found to have different causes. Not surprisingly, the search for a unifying hypothesis to explain all CC or IBS has proven unfruitful. Several phenomena undoubtedly contribute to symptom genesis, including disordered bowel motility (‘spasm’), increased bowel sensitivity (visceral hypersensitivity or hyperalgesia in IBS, hyposensitivity in some with CC), altered cerebral processing of gut events, environmental stressors and intrinsic psychopathology [Quigley, 2003].

While a variety of abnormal electromyographic and motor patterns have been described in the various parts of the gastrointestinal tract in IBS, the specificity of any of these for IBS remains unclear [McKee and Quigley, 1993] and interest has shifted to the role of colorectal sensation as well as dysfunction along the brain–gut axis in the pathogenesis of symptoms in IBS [Bouin et al. 2002].

Prucalopride for constipation

Prucalopride is a highly selective serotonin 5-HT₄ receptor agonist which has been shown to stimulate gut motility in vitro and in vivo [Sanger and Quigley, 2010]. In healthy volunteers, scintigraphic studies demonstrated that prucalopride accelerated whole gut and colonic transit but not gastric emptying or small bowel transit [Bouras et al. 1999]. Among patients with constipation, however, the very same authors using the exact same scintigraphic technique found that prucalopride in doses of 2 or 4 mg daily accelerated whole gut, gastric, small bowel and colonic transit in constipated patients [Bouras et al. 2001]. Importantly, prucalopride did not appear to adversely affect a number of parameters of anorectal motor function or impair rectal sensation in either healthy volunteers or patients with constipation [Sloots et al. 2002; Bouras et al. 2001; Poen et al. 1999; Emmanuel et al. 1998]. In studies of colonic motility, prucalopride has been shown to be stimulatory [De Schryer et al. 2002; Emmanule et al. 2002].

Given the profile of pharmacological effects described for prucalopride in vivo, it should come as no surprise that the major clinical focus of prucalopride has been in constipation [Emmanuel et al. 2002; Camilleri et al. 2008b; Quigley et al. 2009; Tack et al. 2009]. Indeed, each of the three major studies of prucalopride in humans has been in CC [Tack et al. 2009; Quigley et al. 2009; Camilleri et al. 2008b] (Table 1). For reasons related to the transfer of the drug from one company to another, these trials have only been published recently, even though they were actually designed and completed some time ago. These three trials, which became pivotal in terms of regulatory submission, featured a randomized, placebo-controlled, parallel group design. The major inclusion criterion was the presence of CC, defined as two or fewer spontaneous complete bowel movements (SCBMs) per week for at least 6 months prior to screening plus any one of the following: hard/very hard stools, a sensation of incomplete evacuation, or straining, during defecation in relation to at least 25% of bowel movements. After a 2-week baseline period, eligible patients were randomized to either a placebo, or 2 mg or 4 mg of prucalopride for 12 weeks. The primary endpoint, in each study, was the proportion of patients passing at least three SCBMs per week during the 12 weeks of the trial, based on an intention-to-treat analysis. All three trials (which assessed 620, 641, and 713 patients, respectively) demonstrated a significant increase in the proportion of patients achieving at least three SCBMs per week compared with placebo. Response rates ranged from 19.5% to 31% with 2 mg prucalopride, 24% to 28% with 4 mg prucalopride, and 9.6% to 12% with placebo. Clinically relevant and statistically significant improvements were also demonstrated in a number of secondary endpoints, including satisfaction with bowel function, perception of constipation severity, and patient-assessed symptom scores. A validated, disease-specific quality of life instrument (Patient Assessment of Constipation-Quality of Life – PAC-QOL) [Dubois et al. 2010], but not a generic quality of life instrument (Short Form 36 – SF-36), showed significant improvements with prucalopride [Tack et al. 2009; Quigley et al. 2009; Camilleri et al. 2008b]. Even though men and women were enrolled in these studies, over 85% of evaluated patients were female. While this led to the approval of the drug being restricted to women, it needs to be stressed that this should not be taken to imply prucalopride is not effective in men but, rather, that it has not been adequately tested in this gender. Though two doses, 2 mg once daily and 4 mg once daily, were tested in these studies, a dose–response effect was not obvious, thus the recommended dose is 2 mg.

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Table 1.

Main results of the three pivotal trials of prucalopride in gastrointestinal chronic constipation.

Reference	Study design (No. of patients)	Outcomes (2 mg and 4 mg prucalopride versus placebo)
[Camilleri et al. 2008b]	12 weeks (620)	No. of patients achieving
	Prucalopride 2 mg or 4 mg dailyversus placebo	≥3 SCBMs/week: 30.9% and 28.4% versus 12% An increase of ≥1 SCBM/week: 47.3% and 46.6%versus 25.8%
[Quigley et al. 2009]	12 weeks (641)	No. of patients achieving:
	Prucalopride 2 mg or 4 mgdaily versus placebo	≥3 SCBMs/week: 23.9% and 23.5% versus 12.1% An increase of ≥1 SCBM/week: 42.6% and 46.6%versus 27.5%
[Tack et al. 2009]	12 weeks (713)	No. of patients achieving:
	Prucalopride 2 mg or 4 mgdaily versus placebo	≥3 SCBMs/week: 19.5% and 23.6% versus 9.6% An increase of ≥1 SCBM/week: 38.1% and 44.1%versus 20.9%

SCBM, spontaneous complete bowel movement.

CC is not a short-term problem; long-term results are critically important for such a chronic problem. Experience over a longer term is based on open-label follow up, for up to 24 months, of 86% of those patients who had completed the three randomized, double-blind pivotal studies described above [Camilleri et al. 2010]. Improvement in the PAC-QOL observed in the double-blind phase was maintained during open-label treatment for up to 18 months.

These benefits were supported in smaller studies of CC [Emmanuel et al. 2002; Sloots et al. 2002] as well as in studies of special populations: elderly people [Müller-Lissner et al. 2010], those with severe, refractory constipation [Coremans et al. 2003], opioid-induced constipation [Sloots et al. 2010], and constipation related to spinal cord injury [Krogh et al. 2002].

Prucalopride in other motility disorders

To date, there are very limited data on the impact of prucalopride on motility disorders affecting other parts of the gastrointestinal tract [Boecxstaens et al. 2002] and it is certainly too early to assess its potential usefulness in disorders such as gastroparesis, intestinal pseudo-obstruction, functional dyspepsia and, most importantly, IBS-C.

Safety

Given the cardiac adverse event history that led to the withdrawal of the less selective serotonergic agonists, cisapride [Quigley, 2011] and tegaserod [Chan et al. 2009], considerable attention has been paid to the safety profile of prucalopride and to its cardiac toxicity, in particular. In the pivotal studies, which collectively represent the largest experience with the drug, the most common treatment-associated adverse events were headache (25–30% prucalopride; 12–17% placebo), nausea (12–24%; 8–14%), abdominal pain or cramps (16–23%; 11–19%) and diarrhea (12–19%; 3–5%) [Tack et al. 2009; Quigley et al. 2009; Camilleri et al. 2008b]. A majority of these adverse events occurred within the first 24 h of treatment and were short lived [Quigley et al. 2009]. Where reported, the prevalence of serious adverse events was similar for placebo and prucalopride [Tack et al. 2009; Quigley et al. 2009; Camilleri et al. 2008b].

Of critical importance, given the experience with cisapride, is that prucalopride has not been found to interact with either the hERG potassium channel (relevant to cisapride-induced arrhythmias) or 5HT_1B receptors (where tegaserod may have affinity) [Potet et al. 2001] – both postulated to be responsible for the development of adverse cardiovascular effects with other 5HT₄ agonists. Furthermore, no significant hemodynamic or clinically relevant electrocardiographic changes were detected in healthy control studies [Boyce et al. 2009], nor were they detected in any of the major clinical trials [Tack et al 2009, 2008; Quigley et al. 2009; Camilleri et al. 2008b]. In a smaller study conducted in a relatively high-risk population, 89 elderly nursing home residents of whom 80% had a prior history of cardiovascular disease, no significant hemodynamic or electrocardiographic changes were detected. Specifically, there was no evidence of an increase in the incidence of prolongation of the QTc interval [Camilleri et al. 2009].

What is the place of prucalopride in the management of constipation and other gastrointestinal disorders?

To date, high-quality evidence for prucalopride exists only in the area of CC and, then, only for women. Given the aforementioned clinical overlap between CC and IBS, studies in IBS-C are eagerly awaited, as are studies in motor disorders of the foregut and midgut. Efficacy in these latter areas would be of relevance to patients with CC given the frequency with which symptoms such as heartburn, dyspepsia and postprandial fullness occur in these patients.

Currently, prucalopride is approved in a number of countries in Western Europe for use in the management of constipation in women with CC in whom laxatives fail to provide adequate relief; approval is, no doubt, being sought throughout the world. Given the limited number of men included in the pivotal studies, the restriction of approval to women makes sense pending positive data for men. The restriction to laxative failures is also very much in keeping with a number of authoritative guidelines which suggest a step-up approach to the treatment of constipation: beginning with dietary and lifestyle changes, progressing through osmotic laxatives (such as polyethylene glycol derivatives) and reserving pharmacological therapies for people whose condition fails to respond to these steps [Lindberg et al. 2011; Tack et al. 2011; Emmanuel et al. 2009; Brandt et al. 2005]. It must be stressed that there are very few studies comparing the efficacy of a new pharmacological agent with a traditional laxative; for this reason, the real therapeutic gain attributable to prucalopride over and above a laxative remains somewhat conjectural. The one study that compared a new agent, tegaserod, with a laxative, polyethylene glycol, found the latter to be more effective; a salutary lesson [Di Palma et al. 2007].

As a prescription drug for the management of constipation and given the virtual demise of other prokinetic agents for this indication, prucalopride competes primarily with another class of agents: those that stimulate secretion. Two drugs in this class have been extensively studied: the type-2 chloride channel stimulant, lubiprostone and the guanylate cyclase C agonist, linaclotide. Both have demonstrated efficacy in CC and C-IBS [Johnston et al. 2010; Lembo et al. 2010; Drossman et al. 2009; Johanson et al. 2008a, 2008b]. Interestingly, linaclotide has shown an effect against abdominal pain in IBS-C, an effect that seems independent of laxation and is postulated to represent inhibitory activity on sensory afferent nerves [Johnston et al. 2010]. Both drugs are well tolerated, though nausea has been somewhat common with lubiprostone [Drossman et al. 2009; Johanson et al. 2008a, 2008b]. There have been no comparisons with prucalopride.

Conclusions

Prucalopride is a highly selective serotonin 5-HT₄ receptor agonist which acts as a prokinetic in the gut. Data from large randomized, controlled clinical trials indicate that it is effective in CC and offers a new therapeutic alternative for those whose condition fails to respond to conventional laxatives. To date, cardiac toxicity, which bedeviled other drugs in this class, has not been a major issue. Long-term studies and postmarketing data will be critical in assessing the real benefits and risks of this promising compound.