elobixibat and Chronic-Disease

Chronic idiopathic constipation is a common disorder of the gastrointestinal tract that encompasses a wide profile of symptoms. Current treatment options for chronic idiopathic constipation are of limited value; therefore, a novel strategy is necessary with an increased effectiveness and safety. Recently, the inhibition of the ileal bile acid transporter has become a promising target for constipation-associated diseases. Enhanced delivery of bile acids into the colon achieves an accelerated colonic transit, increased stool frequency, and relief of constipation-related symptoms. This article provides insight into the mechanism of action of ileal bile acid transporter inhibitors and discusses their potential clinical use for pharmacotherapy of constipation in chronic idiopathic constipation.

Topics: Animals; Chronic Disease; Constipation; Defecation; Dipeptides; Drug Design; Gastrointestinal Agents; Humans; Ileum; Molecular Targeted Therapy; Organic Anion Transporters, Sodium-Dependent; Symporters; Thiazepines; Treatment Outcome

A number of new medications were recently demonstrated to be more effective than placebo in treating chronic constipation, including the intestinal chloride channel activator lubiprostone, the prokinetic selective 5-HT4 receptor agonist prucalopride and the guanylate cyclase-C agonist linaclotide. Recent publications have also revisited traditional laxatives like PEG. Moreover, a number of pharmacological treatments are in development and these include another guanylate cyclase-C agonist, plecanatide and an ileal bile acid transporter inhibitor, elobixibat.. This review focuses on the pharmacology, efficacy and safety profile of prucalopride, linaclotide, plecanatide and elobixibat.. The possible present or future clinical application of prucalopride, linaclotide, plecanatide and elobixibat in both chronic constipation and irritable bowel syndrome with constipation is reported, and some considerations on the possible role of PEG taking into account recent literature are advanced.

Topics: Benzofurans; Chronic Disease; Constipation; Dipeptides; Humans; Irritable Bowel Syndrome; Laxatives; Natriuretic Peptides; Peptides; Thiazepines

Elobixibat is an oral treatment candidate for chronic constipation with a novel mechanism of action via inhibition of the ileal bile acid transporter. We performed this randomized, double-blind, placebo-controlled, dose-finding phase IIb study in Japanese patients with chronic constipation to determine the optimal clinical dose of elobixibat.. Japanese patients with chronic constipation were randomized to receive elobixibat (5, 10, or 15 mg) or placebo once daily for 2 weeks. The primary efficacy endpoint was the change from baseline in frequency of spontaneous bowel movements at Week 1 of treatment. Secondary endpoints and adverse events were also examined.. Among 226 patients who provided informed consent, 163 patients were randomized and included in the full analysis set. In the 10- and 15-mg groups, frequency of spontaneous bowel movements (±standard deviation) were significantly higher than baseline (5.7 ± 4.2 and 5.6 ± 3.5 times per week, respectively, compared with 2.6 ± 2.9 times per week in the placebo group [P = 0.0005, P = 0.0001, respectively]). Subgroup analysis indicated that elobixibat was equally effective in patients with or without constipation-predominant irritable bowel syndrome. Common adverse events included mild abdominal pain and diarrhea in the elobixibat groups; no serious or severe adverse events occurred. Elobixibat was well tolerated at once-daily oral doses up to 15 mg for 2 weeks.. Our study results suggest that 10 mg of elobixibat is a clinically optimal dose for Japanese patients with chronic constipation.. JapicCTI-142608.

Topics: Administration, Oral; Adult; Aged; Carrier Proteins; Chronic Disease; Constipation; Defecation; Dipeptides; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Male; Membrane Glycoproteins; Middle Aged; Thiazepines; Young Adult

A subset of patients with constipation has reduced colonic bile acid concentrations, which are associated with slow colonic transit. In a previous study, elobixibat, a locally acting ileal bile acid transporter inhibitor, accelerated colonic transit in Japanese patients with functional constipation. In this study, we aimed to determine the efficacy of elobixibat for short-term treatment of chronic constipation, and safety, patient satisfaction, and quality of life with long-term treatment.. We did two phase 3 studies of patients aged 20-80 years in Japan with at least 6 months of chronic constipation, who satisfied Rome III criteria for functional constipation, including fewer than three spontaneous bowel movements per week. The first trial, including patients enrolled at 16 clinics, was a 2-week, randomised, double-blind, placebo-controlled study in which (after a 2-week run-in period) patients were randomly assigned (1:1) to either elobixibat 10 mg/day for 2 weeks or placebo. Randomisation was done with permuted block method (block size six) without stratification. Masking to treatment allocation was achieved with identical appearances of elobixibat and placebo, which were supplied in sealed, opaque containers. Group assignment was concealed from patients, investigators, and analysts. The second trial, including patients enrolled at 34 clinics or hospitals, was an open-label, 1-year study in which all patients received elobixibat; participants could titrate the dose to 5 mg/day or 15 mg/day, or maintain the 10 mg/day dose. In both studies, participants took the study drug as an oral tablet once per day before breakfast. The primary outcome of the 2-week randomised trial was the change from baseline (ie, last week of the 2-week run-in) in the frequency of spontaneous bowel movements during week 1 of treatment. The primary outcome of the 52-week open-label trial was safety (type, severity, and incidence of adverse drug reactions) at all times from treatment initiation. All efficacy analyses were based on the modified intention-to-treat (ITT) population without imputation for any missing data. Safety analyses included all patients who received at least one dose of study drug. These trials are registered with the Japan Pharmaceutical Information Center (numbers JapicCTI-153061 and JapicCTI-153062) and have been completed.. Between Nov 4, 2015, and June 11, 2016, we assigned 133 patients to treatment in the 2-week randomised trial: 70 to elobixibat (69 included in the modified ITT and safety populations) and 63 to placebo. The frequency of spontaneous bowel movements per week during week 1 of treatment was greater with elobixibat (least-squares mean 6·4, 95% CI 5·3-7·6) than with placebo (1·7, 1·2-2·2), p<0·0001). Between Oct 31, 2015, and March 15, 2017, we allocated 341 patients to 52 weeks of elobixibat (340 included in the modified ITT and safety populations). 163 (48%) patients in the 52-week trial had an adverse drug reaction, the most common of which were mild gastrointestinal disorders (in 135 [40%] patients). Inguinal hernia was reported in one patient with elobixibat in the 52-week study as a moderate adverse drug reaction. The most common adverse drug reactions in both trials were mild abdominal pain (13 [19%] patients with elobixibat and one [2%] with placebo in the 2-week randomised trial, and 82 [24%] patients in the 52-week trial) and diarrhoea (nine [13%] patients with elobixibat and none with placebo in the 2-week randomised trial and 50 [15%] in the 52-week trial).. Elobixibat resolved constipation in the short-term, and was well tolerated with both short-term and long-term treatment. The evidence supports the use of this novel approach to increase intracolonic concentrations of endogenous bile acid for the treatment of chronic constipation.. EA Pharma and Mochida Pharmaceutical.

Topics: Abdominal Pain; Adult; Aged; Aged, 80 and over; Bile Acids and Salts; Carrier Proteins; Chronic Disease; Colon; Constipation; Dipeptides; Double-Blind Method; Female; Gastrointestinal Agents; Gastrointestinal Diseases; Gastrointestinal Transit; Humans; Male; Membrane Glycoproteins; Middle Aged; Patient Satisfaction; Quality of Life; Thiazepines; Young Adult

Elobixibat is a minimally absorbed ileal bile acid transporter inhibitor. This study aimed to investigate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of elobixibat in Japanese patients with chronic constipation.. This study consisted of single-dose and multiple-dose tests with a dose-escalating design. Sixty patients including females and males were randomized into five dose levels of elobixibat (2.5, 5, 10, 15 or 20 mg, n = 10 per level) and corresponding placebo (n = 2 per group). A crossover design was used to examine food effect in single-dose test. Patients received test tablets once daily for 14 days in multiple-dose test. We assessed pharmacokinetic-dose proportionality, levels of serum high- and low-density lipoprotein cholesterol and plasma 7α-hydroxy-4-cholesten-3-one (C4), food effect and sex-specific effect. Adverse events and bowel functions such as bowel movements, stool consistency and straining were also evaluated.. Food consumption reduced systemic exposure by around 80% [e.g. least squares mean (ratio of breakfast/no breakfast) maximum plasma concentration: 0.2085 (90% confidence interval, 0.1371-0.3172) at 15 mg] while increased plasma C4 level (P < 0.001). In the multiple-dose test, elobixibat reduced low-density lipoprotein cholesterol and increased C4 whilst unaltering high-density lipoprotein cholesterol level. The increased spontaneous bowel movement frequency was correlated with higher dosage and higher C4 level (R. Elobixibat should be taken before breakfast. Once-daily administration of elobixibat was found to be safe and tolerated up to 20 mg in female and male patients with chronic constipation.

Topics: Administration, Oral; Adult; Carrier Proteins; Cholestenones; Cholesterol, LDL; Chronic Disease; Constipation; Cross-Over Studies; Defecation; Dipeptides; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Food-Drug Interactions; Humans; Ileum; Male; Membrane Glycoproteins; Middle Aged; Placebos; Sex Factors; Tablets; Thiazepines; Treatment Outcome; Young Adult

Elobixibat is a minimally absorbed ileal bile acid (BA) transporter (IBAT) inhibitor in development against chronic constipation (CC) and constipation-predominant Irritable Bowel Syndrome (IBS-C). CC is associated with an increased risk for cardiovascular disease and type2 diabetes mellitus. The objectives of this study were to evaluate metabolic effects of elobixibat. Effects on plasma lipids and BA synthesis were evaluated utilizing a 4-week, placebo-controlled study in patients with dyslipidemia while changes of glucagon-like peptide-1 (GLP-1) by elobixibat was assayed in samples from a 14 day high-dose elobixibat study in patients with CC.. Thirty-six dyslipidemic patients, 21 females, mean age 63 years, were randomized to 2.5 mg or 5 mg elobixibat or placebo once daily for four weeks. The primary endpoint was the change in low density lipoprotein (LDL) cholesterol. Secondary endpoints included other lipid parameters and serum 7α-hydroxy-4-cholesten-3-one (C4), a marker of BA (bile acid) synthesis. Another study, in 36 patients with CC treated with high dose elobixibat; 15 mg or 20 mg/day or placebo for 14 days, was evaluated for changes in GLP-1.. In the dyslipidemia study LDL cholesterol was reduced by 7.4 % (p = 0.044), and the LDL/HDL ratio was decreased by 18 % (p = 0.004). Serum C4 increased, indicating that BA synthesis was induced. No serious adverse events were recorded. In the CC study, GLP-1 increased significantly in both the 15 mg (20.7 ± 2.4 pmol/L; p = 0.03) and the 20 mg group (25.6 ± 4.9 pmol/L; p = 0.02).. Elobixibat reduces LDL cholesterol and LDL/HDL ratio and increase circulating peak GLP-1 levels, the latter in line with increased intestinal BA mediated responses in humans.. ClinicalTrial.gov: NCT01069783 and NCT01038687 .

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bile Acids and Salts; Cholestenones; Cholesterol, HDL; Cholesterol, LDL; Chronic Disease; Constipation; Dipeptides; Dyslipidemias; Female; Glucagon-Like Peptide 1; Humans; Lipids; Male; Middle Aged; Thiazepines; Triglycerides; Young Adult

Elobixibat is a new laxative, but its efficacy and adverse events (AEs) are insufficiently examined compared with those of other laxatives. Hence, by propensity score (PS) matching, we compared the effects and AEs between elobixibat and lubiprostone.. We retrospectively analyzed 1,887 Japanese patients with chronic constipation (CC) treated at our hospital between October 2013 and April 2020. Enrolled patients were divided into three treatment groups, namely, elobixibat (10 mg daily) (E10 group, n = 293), lubiprostone (24 μg daily) (L24 group, n = 772), and lubiprostone (48 μg daily) (L48 group, n = 822), as their first treatment. We then investigated the changes on the weekly average number of spontaneous bowel movements, stool consistency scores (SCSs), and AEs starting from the baseline until the end of the 2-week treatment. To adjust for patients' background, we performed one-to-one nearest neighbor matching without replacement between elobixibat- and lubiprostone-treated patients according to the individual estimated PSs.. After treatment, for SCSs, both the L24 and L48 groups significantly improved compared with the E10 group (p < 0.05), but their stools were soft (Bristol Stool Form Scale: 4.8). Notably, the E10 group had less frequent AEs than the L24 group (26 [9.0%] vs. 43 [14.8%], p = 0.03). Particularly, nausea was significantly less in the E10 group than that in the L48 group (2 [0.7%] vs. 7 [2.4%], p = 0.01).. Elobixibat is a beneficial drug for patients with mildly symptomatic CC and is safe to use, given its few AEs.

Topics: Chronic Disease; Constipation; Defecation; Dipeptides; Female; Humans; Laxatives; Lubiprostone; Male; Middle Aged; Propensity Score; Retrospective Studies; Thiazepines; Treatment Outcome

We aimed to discuss and compare reported adverse reactions and drug add-ons associated with elobixibat and lubiprostone use in chronic constipation treatment, as the safety of these drugs has not been well examined in post-marketing clinical settings.. In this retrospective cohort study, using records of community pharmacies in Japan, we identified new users of elobixibat and lubiprostone. The Japan Pharmaceutical Association sent questionnaires regarding baseline and event data to community pharmacists. The incidence of events and hazard ratio (HR) associated with the study drugs were evaluated.. New users of elobixibat (n = 979) and lubiprostone (n = 829) were identified (mean age: 74 and 77 years; females: 59% and 53%, respectively). Although the crude risk ratio of adverse events for elobixibat was 0.79 (95% confidence interval: 0.63-0.99), there was no significant difference in the HR for any of the common events, including drug add-ons (n ≥ 5), compared with those for lubiprostone.. No new safety concerns have been raised in relation to elobixibat and lubiprostone use for treating chronic constipation, although the HR of different events varied. Further larger-scale study is needed as the estimates for events of small numbers were unstable.

Topics: Aged; Aged, 80 and over; Chloride Channel Agonists; Chronic Disease; Cohort Studies; Constipation; Dipeptides; Female; Gastrointestinal Agents; Humans; Japan; Lubiprostone; Male; Middle Aged; Retrospective Studies; Surveys and Questionnaires; Thiazepines

Chronic idiopathic constipation (CC) is highly prevalent worldwide. A subset of patients with CC have reduced fecal (and by inference, intra-colonic) bile acids (BA). Elobixibat, a locally-acting ileal bile acid transporter (IBAT) inhibitor, leads to increased BA delivery to the colon and represents a new class of treatment for CC. BAs accelerate colonic transit and increase colonic secretion. Therefore, IBAT inhibitors have potential to treat patients with CC. Areas covered: Rationale for IBAT inhibitor in therapeutics, and preclinical and clinical pharmacology of elobixibat: In vitro, elobixibat is a highly potent, selective IBAT inhibitor. In humans, elobixibat accelerated colonic transit. In phase 2A, 2B and 3 studies in CC, elobixibat was efficacious, well tolerated and safe. An open-label, phase 3 trial (52 weeks) confirmed the safety of elobixibat. Elobixibat reduces LDL cholesterol, increases serum GLP-1, and has potential in metabolic syndrome. Expert commentary: Uniquely among current treatments of CC, elobixibat stimulates both motor and secretory functions in the colon. These dual effects suggest that, when approved, elobixibat may be a first-line choice for constipation associated with colonic BA deficiency and a second-line treatment for all patients with CC and constipation-predominant irritable bowel syndrome. Further studies are required to confirm efficacy for relief of CC. Once approved, elobixibat will likely become a second-line choice for treatment of CC.

Topics: Animals; Bile Acids and Salts; Carrier Proteins; Chronic Disease; Clinical Trials as Topic; Constipation; Dipeptides; Dogs; Feces; Gastrointestinal Agents; Gastrointestinal Transit; Humans; Membrane Glycoproteins; Thiazepines