Safety evaluation of lubiprostone in the treatment of constipation and irritable bowel syndrome

Introduction: Lubiprostone is approved in the United States for the treatment of chronic idiopathic constipation and constipation predominant irritable bowel syndrome (IBS-C). Lubiprostone causes secretion of fluid and electrolytes in the small bowel, through the activation of chloride channels, and thereby induces laxation and improvement of bowel functions. It is generally considered to be safe and effective. Common side effects of lubiprostone include nausea, diarrhea, abdominal pain and bloating, and the rare side effect dyspnea. Likely mechanisms for these side effects may be related to lubiprostone's primary action on small bowel secretion and the associated intestinal distension, as well as smooth muscle contraction.

Areas covered: This article reviews the pharmacokinetic and safety profile of lubiprostone, with particular relevance to the two FDA-approved dosages.

Expert opinion: Lubiprostone acts topically in the gut lumen and is almost completely metabolized in the gut lumen. Lubiprostone's M3 metabolite can be detected in low concentrations in the serum and may be responsible for some of its side effects. However, the exact mechanisms by which the side effects are produced are currently unknown.     

Safety evaluation of lubiprostone in the treatment of constipation and irritable bowel syndrome

Introduction: Lubiprostone is approved in the United States for the treatment of chronic idiopathic constipation and constipation predominant irritable bowel syndrome (IBS-C). Lubiprostone causes secretion of fluid and electrolytes in the small bowel, through the activation of chloride channels, and thereby induces laxation and improvement of bowel functions. It is generally considered to be safe and effective. Common side effects of lubiprostone include nausea, diarrhea, abdominal pain and bloating, and the rare side effect dyspnea. Likely mechanisms for these side effects may be related to lubiprostone's primary action on small bowel secretion and the associated intestinal distension, as well as smooth muscle contraction. Areas covered: This article reviews the pharmacokinetic and safety profile of lubiprostone, with particular relevance to the two FDA-approved dosages. Expert opinion: Lubiprostone acts topically in the gut lumen and is almost completely metabolized in the gut lumen. Lubiprostone's M3 metabolite can be detected in low concentrations in the serum and may be responsible for some of its side effects. However, the exact mechanisms by which the side effects are produced are currently unknown.     

Lubiprostone: chronic constipation and irritable bowel syndrome with constipation

Lubiprostone is a bicyclic fatty acid metabolite analogue of prostaglandin E1. The FDA has approved lubiprostone for the treatment of chronic constipation in men and women and the treatment of women with irritable bowel syndrome with constipation (IBS-C). Lubiprostone specifically activates type-2-chloride channels on the apical membrane of epithelial cells. Lubiprostone acts locally within the intestinal tract, is rapidly metabolized and has very low systemic bioavailability. Animal studies have demonstrated that lubiprostone increases gastrointestinal fluid secretion in a dose-dependent manner. Clinical studies performed in men and women with chronic constipation using 24 μg of lubiprostone twice-daily demonstrated objective improvement in stool frequency and consistency, as well as symptoms of straining and incomplete evacuation. A multi-center study of patients with IBS-C found that 8 μg of lubiprostone twice-daily improved both global and individual symptoms of irritable bowel syndrome. Lubiprostone is generally well tolerated and serious adverse events are rare. The most common reported side effects are nausea, headache and diarrhea. This monograph provides a brief overview on chloride channel function in the gastrointestinal tract, describes the structure, function, and pharmacokinetics of lubiprostone, and discusses the safety and efficacy of this new medication for the treatment of chronic constipation and IBS-C.     

Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome – results of two randomized, placebo-controlled studies

Background Effective treatments for irritable bowel syndrome with constipation (IBS‐C) are lacking. Aim To assess the efficacy and safety of lubiprostone in IBS‐C. Methods A combined analysis was performed among 1171 patients with a Rome II diagnosis of IBS‐C in two phase‐3 randomized trials of lubiprostone 8 mcg vs. placebo twice daily for 12 weeks. Using a balanced seven‐point Likert scale ranging from significantly relieved (+3), to significantly worse (?3), patients responded on their electronic diary to the question: ‘How would you rate your relief of IBS symptoms over the past week compared to how you felt before you entered the study?’. The primary efficacy endpoint was the percentage of overall responders. Results Using an intent‐to‐treat analysis with last observation carried forward, a significantly higher percentage of lubiprostone‐treated patients were considered overall responders compared with those treated with placebo (17.9% vs. 10.1%, P = 0.001). Patients treated with lubiprostone reported a similar incidence of adverse events to those treated with placebo. Conclusions The percentage of overall responders based on patient‐rated assessments of IBS‐C symptoms was significantly improved in patients treated with lubiprostone 8 mcg twice daily compared to those treated with placebo. Lubiprostone was well tolerated with a favourable safety profile.     

Tenapanor for the treatment of irritable bowel syndrome with constipation

ABSTRACT

Introduction

Irritable bowel syndrome with constipation is associated with higher rates of functional impairment, as compared to other subtypes of the syndrome. Conventional laxative-based pharmacologic therapy of IBS-C, which is mostly symptom-based, is often unsatisfactory.

Tenapanor represents a first-in-class orally available inhibitor of NHE3, which is minimally absorbed in the GI tract, what constitutes a significant therapeutic benefit, as it may act on the drug target.     

New pharmacological treatment options for irritable bowel syndrome with constipation

Introduction: Constipation predominant irritable bowel syndrome (IBS-C) is a common disorder and accounts for a large number of ambulatory visits. Sensory abnormalities, that is, presence of abdominal pain and discomfort, distinguish IBS-C from chronic idiopathic constipation.

Area covered: This review focuses on the pharmacology, efficacy, safety, and future of prucalopride, YKP-10811, DSP-6952, dexloxiglumide, linaclotide, plecanatide, tenapanor, and elobixibat.

Expert opinion: It is now well established that treatment focusing only on bowel transit provides incomplete relief to patients with IBS-C. Improved understanding of pathophysiology of IBS-C has led to use of sensory end points like complete spontaneous bowel movements and the FDA combined end point (abdominal pain and complete spontaneous bowel movements) in clinical trials. A number of drugs are in development and provide hope for this challenging group of patients. However, because of recent failures secondary to ineffectiveness and/or adverse events, we cautiously await how clinical data play out in larger studies and in clinical practice.     

Clinical trial guidelines for pharmacological treatment of irritable bowel syndrome

Appropriate guidelines for clinical trials in irritable bowel syndrome are needed because of the inadequacy of previously performed trials, the use of new and more adequate patient definition, new emerging pathophysiological models and the unique requirements related to the assessment of treatment outcome that, in the absence of a biological marker, can rely only on the evaluation of clinical manifestations. This consensus report highlights the following points. (a) A 4-week period is considered to be adequate to assess drug efficacy for the control of symptoms. (b) For the cyclic and non-life-threatening nature of the disease, a long-term study of 4-6 months or more of active treatment to establish efficacy is considered to be inappropriate in the large majority of patients. (c) In the initial assessment phase of drug efficacy, the withdrawal effect of treatment can be ascertained during a follow-up period prolonged for a sufficient time (4-8 weeks) after stopping treatment. Subsequent trials with proper withdrawal phase design and duration can then ascertain the drug post-treatment benefit. (d) Considering the intermittent clinical manifestations of irritable bowel syndrome, designing trials with on-demand or repeated cycles of treatment could be envisaged. However, the lack of a definition of what constitutes an exacerbation is a major obstacle to the design of such trials. In the absence of an established gold standard, appropriately justified novel trial designs are welcome. (e) Patients eligible for inclusion should comply with the Rome II diagnostic criteria for irritable bowel syndrome. (f) The main efficacy outcome of the treatment should be based on one primary end-point. (g) The primary efficacy end-point could combine, in a global assessment, the key symptoms (abdominal pain, abdominal discomfort, bowel alterations) of irritable bowel syndrome or rate any single symptom for drugs considered to target specific symptoms. (h) A 50% improvement in the primary efficacy end-point seems to be a reasonable definition of a responder.     

Clinical trial: asimadoline in the treatment of patients with irritable bowel syndrome

Background In models of irritable bowel syndrome (IBS), asimadoline, a kappa‐opioid agonist, improves pain and abnormal bowel function. Aim To evaluate the effects of three doses of asimadoline and placebo in subjects with IBS through a double‐blind, randomized, placebo‐controlled trial. Methods Patients were randomly assigned to receive asimadoline 0.15, 0.5, 1.0 mg or placebo BID for 12 weeks. The primary efficacy measure was number of months of adequate relief of IBS pain or discomfort, with a prospective plan to evaluate adequate relief data by entry baseline pain and subtype. Several other endpoints were also evaluated. Results Five hundred and ninety‐six patients were randomized. In the ITT population, statistically significant improvement on the primary endpoint was not seen. However, in diarrhoea‐predominant IBS patients with at least baseline moderate pain, asimadoline (0.5 mg) produced significant improvement on total number of months with adequate relief of IBS pain or discomfort (46.7% vs. 20.0%), adequate relief of IBS symptoms (46.7% vs. 23.0%), pain scores (week 12: ?1.6 vs. ?0.7), pain free days (42.9% vs. 18.0%), urgency and stool frequency (?2.3 vs. ?0.3). In patients with alternating IBS, significant improvement was seen on adequate relief endpoints. Asimadoline was well tolerated. Conclusion Asimadoline warrants further evaluation as a treatment for IBS.     

Treatment patterns,symptom reduction,quality of life,and resource use associated with lubiprostone in irritable bowel syndrome constipation subtype

Objectives Real-world patient outcomes data is scarce concerning the high disease burden of IBS-C. The aim of this study was to compare patient-reported symptom control, health-related quality of life (HRQoL), resource utilization, and treatment satisfaction of lubiprostone vs non-lubiprostone treatment for irritable bowel syndrome–constipation (IBS-C).

Research design and methods An observational, retrospective US chart review and computer-assisted telephone patient survey was conducted March to August 2013 recruiting women over 18 years old with physician-confirmed IBS-C who had initiated new treatment from inadequate relief of previous treatments and who had been on the new treatment ≥3 months. Multiple IBS-C treatments were permitted. IBS-C severity, time since diagnosis, age, and race were controlled using inverse probability of treatment weighting. Weighted outcomes were compared using t-tests (continuous outcomes) and chi-squared tests (categorical outcomes).

Main outcomes measures Instruments included Patient Assessment of Constipation Symptoms (PAC-SYM) and IBS quality of life (IBS-QoL). A single item assessed current treatment satisfaction.

Results Of 162 patients (mean age 45.9 [SD 15.3] years old, 71% white, 61.1% with moderate IBS-C), 76 switched to lubiprostone and 86 to non-lubiprostone. Groups were similar in clinical and demographic characteristics and previous 30?day IBS-C treatment. After weighting, all PAC-SYM scores were lower for lubiprostone (P?<?0.05). All IBS-QoL subscales were higher for lubiprostone including overall, dysphoria, social reaction, sexual, and relationship scores (P?<?0.05.) More lubiprostone patients reported positive treatment satisfaction (92.3% vs 71.0%, P?<?0.001).

Conclusions In IBS-C patients with inadequate response to previous therapies, lubiprostone improved patient-reported symptom control, treatment satisfaction, and HRQoL. Key limitations include lack of measurement of patient-reported outcomes at treatment start and potential data gaps in chart documentation.     

Dexloxiglumide for the treatment of constipation predominant irritable bowel syndrome

Introduction: Irritable bowel syndrome (IBS) is a multifactorial functional gut disorder, where sensory/motor disturbances seem to play a major role, with no satisfactory treatment for a majority of patients. Cholecystokinin (CCK) is a hormone with several effects on gastrointestinal function, and IBS patients have been shown to produce altered sensory/motor responses to CCK.

Areas covered: Dexloxiglumide is a selective antagonist of the type 1 receptor of CCK, which has demonstrated to revert the CCK mediated effects on gastrointestinal motility and sensitivity. In humans, Dexloxiglumide has been shown to accelerate gastric emptying, slow down transit in the proximal colon, and increase the tolerance to intestinal gas. In phase 2 clinical trials Dexloxiglumide 200 mg tid has demonstrated to be superior to placebo in symptom relief in constipation predominant IBS (IBS-C). In a phase 3 withdrawal study Dexloxiglumide obtained a more sustained effect than placebo. However, these promising effects in IBS-C have not been confirmed in large phase 3 studies so far.

Expert opinion: Dexloxiglumide has demonstrated positive effects on important aspects of gastrointestinal function, like gastric emptying and gas tolerance, that deserves consideration in future studies. However, the available data is insufficient to recommend dexloxiglumide for treatment of IBS-C today.     

Clinical trial: the effect of amitriptyline in patients with diarrhoea-predominant irritable bowel syndrome

Background Irritable bowel syndrome is the most common disorder diagnosed by gastroenterologists. Although several randomized‐controlled trials have assessed the therapeutic role of antidepressant drugs, there is insufficient evidence to support their use. Aim To compare the effects of low‐dose amitriptyline in the treatment of diarrhoea‐predominant irritable bowel syndrome in a double‐blind randomized‐controlled trial. Methods Fifty‐four patients who fulfilled Rome II criteria for diarrhoea‐predominant irritable bowel syndrome were included in this study. Organic causes were ruled out by standard laboratory and radiological tests, and rectosigmoidoscopy. Patients were randomly assigned to receive either 10 mg amitriptyline daily or placebo. Subjects were followed up for 2 months and symptoms were assessed using a questionnaire. Intention‐to‐treat and per‐protocol analysis was performed. Results Fifty patients completed the study. At 2 months, the amitriptyline group showed greater (P < 0.05) reduction in the incidence of loose stool and feeling of incomplete defecation. Patients receiving amitriptyline showed greater complete response, defined as loss of all symptoms, compared with those receiving placebo (68% vs. 28%, P = 0.01). Adverse effects were similar between the two groups. Conclusion Amitriptyline may be effective in the treatment of diarrhoea‐predominant irritable bowel syndrome and at low dose is well tolerated.     

Clinical trial: short- and long-term benefit of relaxation training for irritable bowel syndrome

BACKGROUND: Psychotherapy is effective in treating irritable bowel syndrome, but the effect of relaxation training, a brief psychological group intervention, is not known. AIM: To determine the efficacy of relaxation training in a large cohort of irritable bowel syndrome patients. METHODS: Ninety-eight irritable bowel syndrome patients were included in this randomized controlled trial. Forty-six patients received standard medical care (CON) and 52 received four 90-min sessions of relaxation training in small groups in addition to standard medical care. Irritable bowel syndrome symptom severity, medical consumption and quality of life were assessed at baseline in patients and in 38 healthy controls and evaluated in patients at 3, 6 and 12 months after intervention. RESULTS: Irritable bowel syndrome symptom severity was significantly reduced in the relaxation training group compared to CON at 3, 6 and 12 months after treatment (time-by-treatment interaction, P = 0.002). The number needed to treat for long-term improvement was 5. Quality of life had improved (general health, P = 0.017; health change, P = 0.05). Frequency of doctor visits was reduced (P = 0.039). CONCLUSIONS: Relaxation training is a brief group intervention that significantly improves symptom severity, general health perception and medical consumption in irritable bowel syndrome patients immediately after, as well as 6 and 12 months after intervention.