An update on prucalopride in the treatment of chronic constipation

Abstract

Chronic constipation (CC) is a highly prevalent and often under-appreciated gastrointestinal disorder associated with significant impairment in quality of life. Symptoms of constipation are typically present for a number of years prior to a patient seeking help. Lifestyle modifications followed by, or coupled with, over-the-counter laxatives represent the initial treatment option; however, relief for many is limited and dissatisfaction rates for these approaches remain high. Over recent years, therefore, considerable effort has been exerted on the development of novel pharmacological approaches. Two major targets have emerged, motility and secretion. Research on the former led to the development of a number of prokinetic agents capable of stimulating colonic motility and, thus, accelerating colonic transit. Of these, earlier prototypes such as cisapride and tegaserod, though effective, were ultimately withdrawn due to cardiovascular adverse events due in part to receptor non-selectivity. Highly selective serotonergic receptor agonists have since emerged which appear to be equally effective in stimulating gut motility but are devoid of cardiac side effects. One such agent is prucalopride, which has now been approved for the management of chronic idiopathic constipation in several countries, but not in the United States. Multiple multicenter, randomized placebo-controlled clinical trials have demonstrated superiority for prucalopride compared to placebo in the short to medium term in relieving the major symptoms of constipation in both men and women across a broad spectrum of ages, ethnicities and geographic locations. To date, prucalopride has enjoyed a favorable safety profile and there have been no signals to suggest arrythmogenicity. Efficacy over longer periods of treatment remains to be confirmed. Evidence for efficacy in other forms of constipation, such as opioid-induced constipation and that related to Parkinson’s disease is beginning to emerge; its status in the management of constipation-predominant irritable bowel syndrome or foregut motility disorders, such as gastroparesis, remains to be established.

Introduction

Chronic idiopathic constipation (CC – also referred to as functional constipation) is a common, chronic and often persistent problem with a prevalence rate in the general adult population in North America ranging between 1.9 and 27.2%.¹ It is more common in women^1,2 and its prevalence increases with age.² Though older concepts of constipation were based on stool frequency alone, a more modern definition views CC as a multi-symptom complex; accordingly, the recently published Rome IV criteria define CC as including two or more of the following symptoms:

• (1) straining during >25% of defecations;

• (2) lumpy or hard stools in >25% of defecations;

• (3) sensation of incomplete evacuation in >25% of defecations;

• (4) sensation of anorectal obstruction/blockage in >25% of defecations;

• (5) manual maneuvers (e.g. digital evacuation, support of the pelvic floor) in >25% of evacuations; and

• (6) fewer than three spontaneous bowel movements per week.

Furthermore, these criteria should be fulfilled for the last 3 months and symptom onset should have been at least 6 months prior to diagnosis. In addition, loose stools should be rarely present in the absence of the use of laxatives and, while abdominal pain and/or bloating may be present, these should not be predominant symptoms [i.e. Rome IV criteria for irritable bowel syndrome (IBS) should not be met].³

Given the universal insistence on the use of the Rome criteria in the selection of subjects for inclusion in clinical trials of all functional gastrointestinal disorders, this seismic shift in the definition of CC from a monosymptomatic disorder (<3 bowel movements per week) to the symptom complex described above has major implications for clinical research in this area. Not surprisingly, these same symptoms are now incorporated into the composition of desired outcomes for new therapies; putting it simply, it is no longer adequate for a drug to merely increase stool frequency, it must also address the other symptoms and, ideally, repair any associated deficits in quality of life.

Though supported by, at best, a slim evidence base, lifestyle modifications such as increased fluid intake, exercise and changes in diet⁴ remain the time-honored, sufferer-initiated approaches to the initial management of constipation. An increase in dietary fiber or the addition of fiber supplements are virtually universal components of the regimen; though dietary fiber and fiber supplements can increase stool frequency, there is little or no data on their impact on other symptoms, and side effects such as bloating may limit tolerability.⁵ If symptoms persist, the sufferer next has recourse to one of any number of widely available over-the-counter laxatives and/or stool softeners.⁶ These vary widely in mode of action and efficacy;⁵ many fail to provide adequate relief and lead to high levels of patient dissatisfaction.^6–9 The goal of most laxatives and stool softeners is to increase stool frequency and few have been shown to address the other symptoms included in the syndrome that we now recognize as CC.⁵ Furthermore, lack of predictability and even the induction of fecal incontinence may limit their acceptability, especially in the elderly.⁶

Despite the limited efficacy of self-administered remedies, relatively few sufferers have traditionally sought medical advice and, even then, do so only after enduring many years of symptoms.¹⁰ Not surprisingly, therefore, CC is a growing public health concern related to associated costs of health care utilization, absenteeism and decreased work productivity.¹¹ Patients with constipation of all age groups are known to have lower quality of life scores compared to non-constipated individuals,¹² and these scores are comparable to patients with other chronic conditions such as allergies, musculoskeletal conditions, diabetes and IBS.¹³ Females are more likely to report impaired health-related quality of life scores; other demographic and social factors also impact on quality of life for the CC sufferer.¹² Hence, improvement in quality of life has emerged as an important treatment goal in the management of constipation.

A growing and partially age-related burden of constipation in the community coupled with its impact on many sufferers and the relative ineffectiveness of available remedies¹⁴ has encouraged a search for new, effective and safe options. The fruits of these efforts are now apparent with the arrival in many countries of a range of pharmacological agents directed at various targets for the treatment of CC. One such agent is prucalopride, a highly selective serotonin (5-hydroxytryptamine, 5HT)-4 receptor agonist and prokinetic. Before we focus on a review of the utility of prucalopride in the treatment of CC and the clinical evidence available to support its use, let us first consider the broader context.

5-HT4 receptor agonists in CC

5-HT4 receptors are present throughout the gastrointestinal tract, including the colon, and are primarily located on smooth muscle cells, enterochromaffin cells and the myenteric plexus. A G-protein coupled receptor, the 5-HT4 receptor increases cyclic adenosine monophosphate (cAMP) production when stimulated by serotonin agonists. This results in the modulation of several neurotransmitters and, most importantly, to enhanced release of acetylcholine, the major excitatory neurotransmitter in the gastrointestinal tract.¹⁵ This is thought to be the primary mechanism underlying the prokinetic effects of 5-HT4 receptor agonists.¹⁵ The first drug in this class to be introduced worldwide was cisapride, which enjoyed considerable popularity in the management of a wide spectrum of gastrointestinal disorders ranging from gastro-esophageal reflux (GERD), through gastroparesis to constipation until its withdrawal from the market in 2000 due to an association with cardiac arrhythmias.^16,17 This was a reflection of the low selectivity of the drug and, specifically, its interaction with cardiac human ether a-go-go (hERG) encoded potassium channels at therapeutic doses.¹⁸ These potassium channels are responsible for the rapid phase of the delayed rectifier current in human atria and ventricles; blocking these channels results in a prolongation of the QT interval and an increased risk of arrhythmias. Tegaserod, another partial 5-HT4 agonist which was approved for both CC and IBS with constipation (IBS-C), was withdrawn in 2007 due to reports of rare, but apparently associated, ischemic cardiovascular events.¹⁹ However, a follow-up matched cohort study found no evidence of this increased risk.²⁰ The precise mechanism of the tegaserod cardiovascular effect is unclear, with its affinity for 5 HT1 receptors at therapeutic doses and an effect on platelet aggregation being proposed but not proven as relevant.^17,21 To many, therefore, the verdict on the cardiac toxicity of tegaserod is ‘not proven’.

Chastened by these events, selectivity became the mantra in gastrointestinal serotonin pharmacology and a new generation of highly selective 5-HT4 receptor agonists with a low affinity for hERG channels,²² and an apparently clean cardiovascular safety profile, emerged. To date, that list has included not only prucalopride but also velusetrag (TD-5108), a dihydroquinoline-carboxylic acid derivative and naronapride (ATI-7505), a substituted benzamide. A recent meta-analysis and systemic review on the clinical efficacy and safety profile of the aforementioned 5-HT4 receptor agonists in CC concluded that, despite substantial heterogeneity in all analyses, they were overall more effective than placebo regardless of age, and exhibited a favorable safety profile.²³

Prucalopride: scientific basis its use in the treatment of chronic constipation

Prucalopride is a dihydrobenzofurancarboxamide derivative that is a highly selective 5-HT4 receptor agonist.²⁴ In vitro studies reveal that prucalopride is structurally different from earlier serotonergic prokinetic agents, a feature that conferred not only a high degree of affinity for 5-HT4 receptor, but also precluded interactions with other receptors such as 5-HT3, 5-HT1B/D, motilin and cholecystokinin (CCK) receptors or hERG K⁺ channels at therapeutic doses.²⁴ It is devoid of anticholinergic or anticholinesterase activity.²⁴

Prucalopride stimulates gut motility by interacting with 5-HT4 receptors present throughout the gastrointestinal tract, resulting in acetylcholine release from cholinergic neurons.^25,26 Acetylcholine, in turn, stimulates contraction of the longitudinal muscle layer of the colon and relaxation of the circular muscle layer leading to propulsion of luminal contents.²⁵ In the canine colon, prucalopride induced a dose-dependent stimulation of clustered contractile activity in the proximal colon and inhibition in the distal colon.²⁷ More importantly, prucalopride stimulated giant migratory contractions; the high-amplitude contractions that traverse the length of the colon in an abroad direction and initiate the urge to defecate.²⁷ The absence, diminution in frequency and/or lower amplitude of these contractions has been linked to the pathophysiology of CC.^28,29 Initial studies in healthy human subjects indicated that prucalopride’s prokinetic effects were selective for the colon where an acceleration of overall colonic transit and an increase in proximal colon emptying were observed.³⁰ In subjects with constipation, however, prucalopride not only accelerated colonic transit and enhanced emptying of the proximal colon, but also accelerated gastric emptying and small bowel transit.³¹ In a more recent study, prucalopride was shown not only to increase frequency of giant or high-amplitude contractions in the colon, but also to augment their amplitude, propagation distance and velocity; effects that were all significantly greater than those observed with polyethylene glycol (PEG) 3350 plus electrolytes.³²

Prucalopride is not extensively metabolized in the body and does not influence the function of cytochrome P450 or P glycoprotein; hence, it does not have clinically significant interactions with other drugs.³³ While prucalopride has been shown to interact with cardiac hERG potassium channels, blockade occurs only at very high concentrations; 150 times greater than the therapeutic dose.³⁴ In contrast to cisapride and tegaserod, prucalopride did not demonstrate positive inotropic effects on human isolated myocardial trabeculae. In human atrial myocytes and only at doses that were markedly supratherapeutic, prucalopride acted as a partial agonist of L-type calcium channels.³⁵ However, there were no effects on late repolarizations or the refractory period and there was no evidence of any arrhythmic activity.³⁵

Prucalopride: clinical evidence in chronic idiopathic constipation

Based on the aforementioned effects of prucalopride on colonic motility and transit,^30–32 it should come as no surprise that a major clinical focus has been on its therapeutic role in constipation. Efficacy, tolerability, safety and impact on quality of life have been demonstrated in a number of large, randomized, placebo-controlled trials³⁶ which have led to the approval of prucalopride in several countries, with the usual recommended dose being 2 mg per day in patients under 65 years of age and 1 mg per day in patients over 65 years. Of particular importance are seven pivotal multicenter, double-blind, phase III and IV, placebo-controlled randomized clinical studies which are summarized in Table 1.^37–43

Table 1.

Pivotal clinical trials.

Reference	Study design	Study duration	Sample size	Primary endpoint: ⩾3 SCBM/week (proportion of patients)	Secondary endpoint: ↑ ⩾1 SCBM (proportion of patients)
Camilleri et al., 200837	2 mg or 4 mg daily versus placebo	12 weeks	620	Week 12: 30.9%, * 28.4% * versus 12%	Week 12: 47.3%, * 46.6% * versus 25.8%
Tack et al., 200938	2 mg or 4 mg daily versus placebo	12 weeks	713	Week 12: 19.5%, * 23.6% * versus 9.6%	Week 12: 38.1%, * 44.1% * versus 20.9%
Quigley et al., 200939	2 mg or 4 mg daily versus placebo	12 weeks	641	Week 12: 23.9%, * 23.5% * versus 12.1%	Week 12: 42.6%, * 46.6% * versus 27.5%
Müller-Lissner et al., 201040	1 mg, 2 mg or 4 mg daily versus placebo	4 weeks	300	Week 1: 42.1%, 43.8%, 48.7% * versus 26.1% Week 4: 43.7%, 37.5%, 30.6% versus 24.6%	Week 1: 61.8, * 63.0, * 68.4% * versus 40.6 Week 4: 59.2%, * 48.6%, 45.8% versus 33.8%
Ke et al., 201241	2 mg versus placebo	12 weeks	501	Week 12: 33.3% * versus 10.3%	Week 4: 34.5% * versus 11.1%
Yiannakou et al., 201542	2 mg versus placebo	12 weeks	374	Week 12: 37.9 * versus 17.7%	Week 12: 27.7% * versus 12.2%
Piessevaux et al., 201543	2 mg versus placebo	24 weeks	361	Week 12: 25.1% versus 20.1% Week 24: 25.1% versus 20.7%	Week 24: 48% versus 42%

Prucalopride results in bold. * indicates that the result for that prucalopride dose was significantly superior to placebo.

SCBM, spontaneous complete bowel movement.

The first three of these trials,^37–39 which formed the basis for applications for regulatory approval in several jurisdictions, had a similar study protocol and included adult patients (>18 years) of either sex with chronic idiopathic constipation – defined as two or fewer spontaneous complete bowel movements (SCBMs) per week for at least 6 months before the screening visit. In addition, the enrolled patients were required to have either hard/very hard stools, a sensation of incomplete evacuation or straining with defecation with at least 25% of bowel movements. Patients were not included if their constipation was due to secondary causes such as drugs, endocrine, neurologic or metabolic diseases or surgery. After a 2-week run-in period, patients were randomized to receive either 2 or 4 mg prucalopride or placebo for a 12-week period. The primary efficacy endpoint was the proportion of patients having three or more SCBMs in a week. The main secondary endpoint was the percentage of patients with an average increase of one or more spontaneous complete bowel movement above baseline. All three trials demonstrated that those treated with prucalopride experienced significantly superior outcomes in comparison to placebo for the primary as well as the main secondary endpoint.^37–39 Significantly superior outcomes were also seen in other secondary endpoints: the average number of SCBMs in a week, the number of bowel movements with normal consistency, the median time to first bowel movement, the percentage of bowel movements with severe or very severe straining and the percentage of patients satisfied or very satisfied with their treatment. Using validated questionnaires, the Patient Assessment of Symptoms questionnaire (PAC-SYM) and Patient Assessment of Quality of Life (PAC-QOL) questionnaire,^44,45 these studies also assessed treatment impacts on quality of life. At week 12, the proportion of patients with an improvement of 1 or more point on the PAC-QOL satisfaction score was significantly greater among patients receiving prucalopride in a dose of 2 mg or 4 mg than among those randomized to placebo.^37–39,46 Overall improvement was also observed in patient symptoms using the PAC-SYM tool.^37,39,46 It should also be noted that results for the 2 and 4 mg doses were similar in all three trials – thus the choice of 2 mg for clinical use.

Given the known demographics of constipation, as well as the theoretical risk of adverse events in the elderly, Müller-Lissner and colleagues evaluated the efficacy, safety and effect on quality of life of prucalopride in three doses − 1, 2 and 4 mg – over 4 weeks in patients over 65 years of age with CC.⁴⁰ This study recruited elderly patients from 48 centers in different countries. In terms of the primary endpoint, efficacy was observed only with the highest dose, 4 mg, and only at week 1. In contrast, efficacy for prucalopride was significantly greater than placebo at all doses at week 1 and for the 1 mg dose at weeks 4 for the main secondary efficacy endpoint (the proportion of patients with an average increase of one or more SCBMs per week above baseline). Given the similar and, in terms of some endpoints, superior efficacy for the 1 mg dose in comparison to 2 mg daily, and the slower elimination of prucalopride in the elderly,⁴⁷ 1 mg became the recommended initial dose in the elderly.

Even though the three pivotal trials were open to both genders, 85% of all enrolled patients were female;^37–39 consequently, a randomized, multicenter placebo-controlled clinical trial was conducted to evaluate prucalopride in males with CC.⁴² A total of 374 patients were enrolled in this study and, in concordance with previous trials, significantly more patients in the prucalopride group achieved the primary efficacy endpoint. Men randomized to prucalopride were also more likely to experience an improvement of at least 1 point on the PAC-QOL satisfaction subscale score.⁴²

A phase III randomized clinical study among patients with CC from the Asia-Pacific region also confirmed the superiority of prucalopride in a dose of 2 mg over placebo in achieving an average of three or more SCBMs per week over the 12-week treatment period.⁴¹

All of the trials described above demonstrated efficacy for prucalopride in the treatment of CC for up to 12 weeks. However, CC is, by definition, long-term, with patients typically experiencing symptoms over years rather than weeks. Sustained satisfaction with continued treatment with prucalopride was reported in two long-term open-label follow-up studies⁴⁸ that enrolled patients from three of the above-mentioned clinical trials^37–39 and in another open-label study.⁴⁹ However, the primary efficacy endpoint in these long-term studies was patient satisfaction evaluated using PAC-QOL, rather than improvement in SCBM frequency. Hence, a randomized placebo-controlled clinical trial was conducted to evaluate the efficacy of prucalopride over a 24-week period.⁴³ This trial has gained significant attention because contrary to previous studies, treatment with 2 mg prucalopride in this trial showed no statistically significant improvement in the proportion of patients achieving three or more SCBMs per week in comparison to placebo over the first 12 weeks or over the complete 24-week period. In addition, the proportion of patients with an improvement in the PAC-SYM score of at least 1 point was significantly greater in the placebo group when compared to the treatment group (40.1% and 29.9% respectively, p = 0.024). Furthermore, no statistically significant improvement in PAC-QOL score was seen in the treatment group compared to placebo. To date and despite an extensive evaluation, a plausible explanation for the inconsistency between the results of this trial and the previous large pivotal studies has yet to emerge.^36,43 However, until future studies demonstrate continued efficacy over longer treatment periods, the long-term efficacy of prucalopride must be questioned.

How does prucalopride compare with laxatives or other prescription drugs for constipation?⁵⁰ There have been few comparative studies and certainly none against the pro-secretory agents, the guanylate cyclase C agonists linaclotide⁵¹ and plecanantide⁵² or the type-2 chloride channel activator, lubiprostone⁵³; all of which are approved for the treatment of CC in the United States.

In a secondary analysis of the three pivotal studies, Tack and colleagues found that among patients described as laxative failures at baseline (the majority of the total patient population) prucalopride was, at the very least, just as effective as among those who had reported a response to laxatives.⁵⁴ However, in the one randomized trial to date that directly compared prucalopride to another agent, in this case PEG 3350 plus electrolytes, both treatments were equally effective against the primary endpoint (the proportion of patients having ⩾3 SCBMs during the last treatment week).⁵⁵ Indeed, the PEG preparation demonstrated superiority for most secondary variables.⁵⁵

Despite initial promise,⁵⁶ a well-conducted randomized, placebo-controlled study among 213 children with CC found no benefit for 2 mg prucalopride over placebo in an 8-week study.⁵⁷

Safety and tolerability of prucalopride

The most frequent treatment-associated adverse effects reported with prucalopride in adults have been diarrhea, headache, nausea and abdominal discomfort;⁵⁸ these were most prominent on the first day of treatment.⁵⁸ According to an integrated analysis of phase III clinical trials of prucalopride, Asians reported a higher frequency of diarrhea compared to non-Asians, but a lower frequency of other treatment-associated adverse effects, including headache, abdominal pain and nausea.⁵⁸ In healthy human volunteers, therapeutic and supratherapeutic doses of prucalopride were not associated with significant QT interval prolongation;⁵⁹ in clinical trials reported to date there were no clinically relevant cardiac side effects in the clinical trials.⁵⁸

Prucalopride appears to be also safe in the elderly. In a dose-escalation (from 0.5 to 2 mg) study among 89 nursing home residents, of whom 89% had a history of cardiovascular disease, the most frequent adverse events were headache and diarrhea; no electrocardiographic changes or cardiac events were recorded.⁶⁰

Prucalopride is not metabolized to any great extent in man and is excreted largely unchanged and predominantly in the urine.^61,62 Consequently, clearance was significantly reduced in patients with severe renal impairment and a halving of the usual adult dose (2 mg daily) is thus recommended.⁶³ Though hepatic metabolism is minimal, a similar strategy is also recommended for patients with advanced liver disease.⁶² Prucalopride does not interfere with the bioavailability of oral contraceptive medications.⁶⁴

Single case reports have described a serious neuro-psychiatric event⁶⁵ and acute tubular necrosis⁶⁶ in patients prescribed prucalopride; a causal relationship has not been established in either case.

Other potential indications

Chronic constipation frequently overlaps with other functional gastrointestinal disorders such as IBS, dyspepsia and GERD; indeed, the differentiation of CC from IBS-C may be difficult in the clinic. Studies of prucalopride in IBS-C are notable, surprisingly, for their absence; that prucalopride might be effective in this context is suggested by its ability to reduce intestinal gas-related symptoms, so common in IBS, though without accelerating gas transit.⁶⁷ Effects on gastric emptying^31,68 and esophageal clearance⁶⁸ suggest the potential for positive effects on gastroparesis and gastro-esophageal reflux, respectively; neither has been formally tested as yet. Pathological disorders of the enteric neuromuscular apparatus, such as chronic idiopathic pseudo-obstruction, may also feature constipation; here again, prucalopride has demonstrated some efficacy.⁶⁹ The demonstration of a neuroprotective effect of prucalopride on human enteric neurons adds a further dimension to the potential use of this drug in these rare but serious motility disorders.⁷⁰ Ileus, the acute form of pseudo-obstruction, also responds to prucalopride.⁷¹

Constipation may complicate several neurological disorders. In a small pilot study conducted on patients with CC secondary to spinal cord injury, prucalopride was effective in reducing the median colonic transit time and improving frequency of bowel movements.⁷² Data on other neurological disorders, despite theoretical promise in Parkinson’s disease, for example, ⁷³ is limited but there are hints of efficacy.^74,75

Opioid-induced constipation (OIC) has emerged as a major clinical challenge in the United States and elsewhere.⁷⁶ In a phase II, placebo-controlled trial, prucalopride in both the 2 mg and 4 mg doses was more effective in increasing the frequency of bowel movements above baseline in patients with chronic non-cancer pain suffering from OIC. It also improved other symptoms of constipation as rated by PAC-SYM and PAC-QOL scores and was safe and well tolerated, with nausea and abdominal pain being the most frequent adverse events.⁷⁷

In an in vivo and in vitro study on the role of 5-HT4 agonists (mosapride and prucalopride) in regulating glucose control, it was found that 5-HT4 receptors are located on B-cells in pancreatic islets and that the activation of these receptors stimulates insulin secretion and reduces blood glucose levels.⁷⁸ The clinical implications of this finding remain to be defined, though it should be remembered that constipation is the most common gastrointestinal complaint among those with diabetes.⁷⁹

Conclusions: the positioning of prucalopride in the management of chronic constipation

So what have we learned? From all of the studies performed to date, one can conclude that prucalopride is an effective and safe option for the treatment of CC in both men and women in the short term (up to 12 weeks). Long-term efficacy has yet to be demonstrated and its efficacy in children and the elderly is also unclear, though, yet again, safety does not appear to be an issue in these specific populations either. Particularly reassuring, given past experience with drugs in this class, is the absence of a worrying cardiac signal. Where available, prucalopride should be considered in the management of the adult patient with constipation, regardless of subtype or symptom pattern,⁸⁰ who has failed to obtain relief from laxatives. Preliminary pharmaco-economic data from the Netherlands⁸¹ and Ireland⁸² suggest that this may be a cost-effective approach. There is currently no data on the relative efficacy of prucalopride and the pro-secretory agents; in theory, prucalopride, by virtue of its positive effects on foregut motility, might have an edge among those with overlapping upper gastrointestinal symptoms.⁸³