Ileal Bile Acid Transporter Research Articles

PS-194-Effects of the ileal bile acid transport inhibitor A4250 on serum bile acids, pruritus and sleep in patients with Alagille syndrome: Phase 2 study results

PS-194-Effects of the ileal bile acid transport inhibitor A4250 on serum bile acids, pruritus and sleep in patients with Alagille syndrome: Phase 2 study results

FRI-060-Effects of the ileal bile acid transport inhibitor A4250 on pruritus and serum bile acids in patients with biliary atresia: phase 2 study results

FRI-060-Effects of the ileal bile acid transport inhibitor A4250 on pruritus and serum bile acids in patients with biliary atresia: phase 2 study results

Autotaxin, bile acid profile and effect of ileal bile acid transporter inhibition in primary biliary cholangitis patients with pruritus.

Pruritus is a common symptom in patients with primary biliary cholangitis (PBC) for which ileal bile acid transporter (IBAT) inhibition is emerging as a potential therapy. We explored the serum metabonome and gut microbiota profile in PBC patients with pruritus and investigated the effect of GSK2330672, an IBAT inhibitor. We studied fasting serum bile acids (BAs), autotaxin and faecal microbiota in 22 PBC patients with pruritus at baseline and after 2weeks of GSK2330672 treatment. Control group included 31 asymptomatic PBC patients and 18 healthy volunteers. BA profiling was done by ultra performance liquid chromatography coupled to a mass spectrometry (UPLC-MS). Faecal microbiomes were analysed by 16S ribosomal RNA gene sequencing. In PBC patients with pruritus, serum levels of total and glyco-conjugated primary BAs and autotaxin were significantly elevated. Autotaxin activity correlated significantly with tauro- and glyco-conjugated cholic acid (CA) and chenodeoxycholic acid (CDCA), both at baseline and after GSK2330672. GSK2330672 significantly reduced autotaxin and all tauro- and glyco- conjugated BAs and increased faecal levels of CA (P=0.048) and CDCA (P=0.027). Gut microbiota of PBC patients with pruritus was similar to control groups. GSK2330672 increased the relative abundance of Firmicutes (P=0.033) and Clostridia (P=0.04) and decreased Bacteroidetes (P=0.033) and Bacteroidia (P=0.04). Pruritus in PBC does not show a distinct gut bacterial profile but is associated with elevated serum bile acid and autotaxin levels which decrease after IBAT inhibition. In cholestatic pruritus, a complex interplay between BAs and autotaxin is likely and may be modified by IBAT inhibition.

Efficacy, long-term safety, and impact on quality of life of elobixibat in more severe constipation: Post hoc analyses of two phase 3 trials in Japan.

BackgroundIn two phase 3 trials, elobixibat, a locally acting ileal bile acid transporter inhibitor, resolved constipation and was well tolerated in Japanese patients with chronic constipation. We analyzed the efficacy, safety, and impact on quality of life (QOL) of elobixibat in patients with symptomatically more severe constipation in the two phase 3 trials.MethodsThis post hoc analysis of elobixibat treatment outcomes included data from a 2‐week, randomized, placebo‐controlled, phase 3 trial (10 mg/d), and a 52‐week, open‐label trial (5‐15 mg/d) in subgroups with severe constipation defined as ≤2 spontaneous bowel movements (SBMs) and ≤3 Bristol Stool Form Scale score during the second week of the 2‐week run‐in period. We also analyzed the rates of abdominal pain, diarrhea, and QOL in subgroups according to sex, presence of constipation‐predominant irritable bowel syndrome (IBS‐C) and side effects.Key ResultsIn patients with severe constipation, there was significant improvement in the 10 mg elobixibat group compared to the placebo group in change in SBMs from baseline at week 1 (primary endpoint) of the 2‐week trial. The differences between groups were reduced in patients with more severe constipation. Increasing the dose to 15 mg was effective for more severe constipation in improving the number of SBMs per week in the 52‐week trial. Overall, elobixibat was well tolerated and improved QOL scores, irrespective of gender, presence of IBS‐C or side effects.Conclusions & InferencesElobixibat is effective for symptomatically severe constipation, is well tolerated and improves QOL, irrespective of potentially confounding patient characteristics.

Defining the role of Parasutterella, a previously uncharacterized member of the core gut microbiota.

The genus of Parasutterella has been defined as a core component of the human and mouse gut microbiota, and has been correlated with various health outcomes. However, like most core microbes in the gastrointestinal tract (GIT), very little is known about the biology of Parasutterella and its role in intestinal ecology. In this study, Parasutterella was isolated from the mouse GIT and characterized in vitro and in vivo. Mouse, rat, and human Parasutterella isolates were all asaccharolytic and producers of succinate. The murine isolate stably colonized the mouse GIT without shifting bacterial composition. Notable changes in microbial-derived metabolites were aromatic amino acid, bilirubin, purine, and bile acid derivatives. The impacted bile acid profile was consistent with altered expression of ileal bile acid transporter genes and hepatic bile acid synthesis genes, supporting the potential role of Parasutterella in bile acid maintenance and cholesterol metabolism. The successful colonization of Parasutterella with a single environmental exposure to conventional adult mice demonstrates that it fills the ecological niche in the GIT and contributes to metabolic functionalities. This experiment provides the first indication of the role of Parasutterella in the GIT, beyond correlation, and provides insight into how it may contribute to host health.

Effect of geniposidic acid on hepato-enteric circulation in cholestasis rats through Sirt1-FXR signaling pathway

To investigate the effects of geniposidic acid( GPA) on hepato-enteric circulation in cholestasis rats,and to explore the mechanism based on the sirtuin 1( Sirt1)-farnesol X receptor( FXR) pathway,sixty SD rats were randomly divided into 6 groups:blank control group,ANIT model group,ursodeoxycholic acid group( 100 mg·kg~(-1)·d-1 UDCA),and GPA high,medium and low( 100,50 and 25 mg·kg~(-1)·d-1) dosage groups,10 rats in each group. Corresponding drugs were intragastrically( ig) administered for10 days. After administration on day 8,all rats except blank rats were administered with 65 mg·kg~(-1)α-naphthalene isothiocyanate( ANIT) once. After the last administration,the serum levels of alanine aminotransferase( ALT),glutamine oxalacetate aminotransferase( AST),gamma-glutamyltransferase( γ-GGT),alkaline phosphatase( ALP),total bilirubin( TB) and total bile acid( TBA)were measured,and the mRNA transcription levels of Sirt1,FXR,multidrug resistant associated protein 2( MRP2),bile salt export pump( BSEP),sodium taurocholate contractible polypeptide( NTCP) in liver and apical sodium bile acid transporter( ASBT),ileum bile acid binding protein( IBABP) in ileum were detected by reverse transcription-polymerase chain reaction( RT-PCR). The protein expression levels of Sirt1,FXR and NTCP were detected by Western blot; the expression of MRP2,BSEP in liver and ASBT,IBABP in ileum were determined by immunofluorescence three staining. Primary rat hepatocytes were cultured in vitro to investigate the inhibitory effect of GPA on a potent and selective Sirt1 inhibitor( EX 527),and the mRNA and protein expression levels of Sirt1 and FXR were detected by RT-PCR and Western blot. GPA significantly decreased the levels of ALT,AST,γ-GGT,ALP,TB,TBA in serum( P<0.01) and improved the pathological damage of liver tissues in ANIT-induced cholestasis rats; significantly increased the mRNA and protein expression levels of Sirt1,FXR,MRP2,BSEP,NTCP in liver and ASBT,IBABP in ileum( P< 0.01). In vitro primary hepatocytes experiment indicated that the gene and protein expression levels of FXR and Sirt1 were noticeably improved by GPA in primary hepatocytes inhibited by EX-527( P<0.01). It was found that the improvement of GPA was in a dose-dependent manner. GPA could improve bile acid hepatointestinal circulation and play a liver protection and cholagogu role in cholestasis rats induced by ANIT.The mechanism may be that GPA activated FXR by regulating Sirt1,a key regulator of oxidative stress injury,and then the activated FXR could regulate protein of bile acid hepato-enteric circulation.

VII. How to Treat Chronic Constipation with Intestinal Secretagogues or Inhibitor of Ileal Bile Acid Transporter

慢性便秘症においては，偏食，食事量のアンバランス，夜食，睡眠不足，運動不足ならびに心理社会的ストレスが症状の増悪因子であるため，これらの除去・調整を実施する．これらで不十分であれば，食事療法を基本とし，運動療法を加えるが，治療効果が確実なのは適切な薬物療法である．近年，使用可能となった2種類の上皮機能変容薬及び1種類の胆汁酸トランスポーター阻害薬の3種類の薬物は，それぞれ異なる分子を標的としており，エビデンスレベルも高い．それぞれの特性を知り，便秘患者の診療に役立てることが望まれる．

Pharmacological characteristics and clinical study results of ileal bile acid transporter inhibitor elobixibat (GOOFICE® tablet 5 mg)

Elobixibat is a novel small-molecule that acts as an inhibitor of the ileal bile acid transporter (IBAT), and used for chronic constipation in Japan. Elobixibat selectively inhibited IBAT in vitro, and dose-dependently inhibited the absorption of bile acids in vivo. Also, elobixibat dose-dependently increased wet fecal weight in a rat loperamide-induced constipation model. The drug-drug interaction study suggested that elobixibat may have a clinically slight inhibitory effect on P-glycoprotein. In a phase II study with chronic constipation, the recommended dosage for oral administration of elobixibat once daily was estimated to be 10 mg. In a phase 3 study with chronic constipation, the superiority of the elobixibat 10 mg group to the placebo group was demonstrated in the change from baseline (ie, the last week of the 2-week run-in period) in the frequency of spontaneous bowel movements per week during the first week of treatment set as the primary endpoint. In a long-term study in which elobixibat was administered to patients with chronic constipation for 52 weeks, the ameliorating effects of elobixibat on constipation were observed from the first week of treatment and maintained well until week 52. In addition, the safety/tolerability of elobixibat administered once daily for 52 weeks was considered to be acceptable. Therefore, elobixibat has a mechanism of action that differs from any of the existing therapeutic agents for constipation and is expected to become one of the new treatment options for chronic constipation.

Diet-Induced Dysbiosis and Genetic Background Synergize With Cystic Fibrosis Transmembrane Conductance Regulator Deficiency to Promote Cholangiopathy in Mice.

The most typical expression of cystic fibrosis (CF)–related liver disease is a cholangiopathy that can progress to cirrhosis. We aimed to determine the potential impact of environmental and genetic factors on the development of CF‐related cholangiopathy in mice. Cystic fibrosis transmembrane conductance regulator (Cftr)−/− mice and Cftr +/+ littermates in a congenic C57BL/6J background were fed a high medium‐chain triglyceride (MCT) diet. Liver histopathology, fecal microbiota, intestinal inflammation and barrier function, bile acid homeostasis, and liver transcriptome were analyzed in 3‐month‐old males. Subsequently, MCT diet was changed for chow with polyethylene glycol (PEG) and the genetic background for a mixed C57BL/6J;129/Ola background (resulting from three backcrosses), to test their effect on phenotype. C57BL/6J Cftr −/− mice on an MCT diet developed cholangiopathy features that were associated with dysbiosis, primarily Escherichia coli enrichment, and low‐grade intestinal inflammation. Compared with Cftr +/+ littermates, they displayed increased intestinal permeability and a lack of secondary bile acids together with a low expression of ileal bile acid transporters. Dietary‐induced (chow with PEG) changes in gut microbiota composition largely prevented the development of cholangiopathy in Cftr −/− mice. Regardless of Cftr status, mice in a mixed C57BL/6J;129/Ola background developed fatty liver under an MCT diet. The Cftr −/− mice in the mixed background showed no cholangiopathy, which was not explained by a difference in gut microbiota or intestinal permeability, compared with congenic mice. Transcriptomic analysis of the liver revealed differential expression, notably of immune‐related genes, in mice of the congenic versus mixed background. In conclusion, our findings suggest that CFTR deficiency causes abnormal intestinal permeability, which, combined with diet‐induced dysbiosis and immune‐related genetic susceptibility, promotes CF‐related cholangiopathy.

Elobixibat for the treatment of constipation

ABSTRACTIntroduction: 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.

Ileal Bile Acid Transporter Inhibition for the Treatment of Chronic Constipation, Cholestatic Pruritus, and NASH.

Bile acids are synthesized from cholesterol in the liver, excreted with bile into the duodenum, almost completely taken up again in the distal ileum and finally returned to the liver with portal blood in a process termed enterohepatic circulation. Bile acid synthesis, excretion, and reuptake are tightly regulated. The apical sodium-dependent bile acid transporter [ASBT; also known as ileal bile acid transporter (IBAT) and SLC10A2] is pivotal for the almost complete reabsorption of conjugated bile acids in the ileum. Dysfunctional IBAT may be the cause of bile acid diarrhea. Pharmacological IBAT inhibition results in an increased bile acid load in the colon and subsequently a lower bile acid pool, which is associated with improved liver histology in animal models of cholestatic liver disease and non-alcoholic steatohepatitis (NASH). In humans, IBAT inhibitors have been tested in clinical trials with widely different indications: in patients with idiopathic chronic constipation, an increased number of bowel movements was observed. In adult and pediatric cholestatic liver diseases with pruritus, various IBAT inhibitors showed potential to improve itching. Adverse events of IBAT inhibitors, based on their mode of action, are abdominal pain and diarrhea which might patients to withdraw from study medications. So far, no data are available of a study of IBAT inhibitors in patients with NASH. In this review we summarize the preclinical and most recent clinical studies with various IBAT inhibitors and discuss the difficulties that should be addressed in future studies.

Elobixibat, an ileal bile acid transporter inhibitor, induces giant migrating contractions during natural defecation in conscious dogs.

Chronic constipation affects 14%-17% of the population. Elobixibat, a novel, ileal bile acid transporter (IBAT) inhibitor, has been approved as a new chronic constipation drug in Japan in January 2018. The present study aimed to examine the pharmacological effects of elobixibat on colonic motility in conscious dogs using a telemetry system. Six male beagle dogs were surgically implanted with strain gauge force transducers for gastrointestinal (GI) motility recording. The motility index was calculated from GI motility at each recording site in conscious and nonrestraint dogs. The fasted dogs were orally administered elobixibat (3, 10, or 30mg kg-1 ) or 30mg kg-1 of sennoside as positive control or vehicle using a crossover design and washout period of more than 6days. One hour after drug administration, the dogs were fed chow, and GI motility and defecation were observed for 10hours; GI motility was quantified to calculate giant migrating contractions (GMCs). Fecal bile acids (BAs) were determined as well. Elobixibat and sennoside significantly increased the number of defecations, fecal wet weight, and water content within 10hours after administration. Elobixibat dose-dependently decreased the time to first bowel movement, increased the amount of total fecal BAs, and rapidly induced mild GMCs during defecation; however, higher strength of GMCs was observed with sennoside. Elobixibat induces bowel movements faster than sennoside through a different mechanism. Elobixibat locally inhibits IBAT in the ileal lumen, leading to elevated fecal BAs in the colon and induced mild GMCs during defecation.

Elobixibat, the first-in-class Ileal Bile Acid Transporter inhibitor, for the treatment of Chronic Idiopathic Constipation

ABSTRACTIntroduction: Elobixibat is the first in class ileal bile acid transporter (IBAT) inhibitor. IBAT inhibitors block ileal absorption of bile acids by: (1) interrupting the enterohepatic circulation of bile resulting in a fall in serum cholesterol and (2) increasing the delivery of bile acids into the colon. Increasing colonic bile acids causes mucosal fluid secretion and enhances colonic motor activity. Changes in colonic physiology may be useful in treating constipation.Areas covered: In this review, the author reviews the prevalence and medical cost of Chronic Idiopathic Constipation (CIC) and the heterogeneity of the CIC patient population as a complicating factor in drug development and clinical care. He also reviews the history of Bile Acid cathartics and the complex pharmacophysiology of bile therapy with fluid and electrolyte shifts, colonic motor function changes and mucosal immunologic activation. Finally, the author reviews elobixabat development and the clinical trials that demonstrate improvement in constipation.Expert opinion: The early phases of elobixibat development provide confirmation of high IBAT binding affinity which translates into the expected inhibition of enterohepatic bile acid circulation and enhanced delivery of ileal bile acids to the colon associated with expected physiological changes. Elobixibat as a treatment of CIC appears promising.

Effect of single and multiple doses of elobixibat, an ileal bile acid transporter inhibitor, on chronic constipation: A randomized controlled trial.

AimsElobixibat 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.MethodsThis 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.ResultsFood 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 (R2 = 0.5929 at Week 2). Adverse events were mainly gastrointestinal symptoms, most of which were mild.ConclusionsElobixibat 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.

A novel bioluminescence-based method to investigate uptake of bile acids in living cells.

Bile acid transporters, including the ileal apical sodium-dependent bile acid transporter (ASBT) and the hepatic sodium-taurocholate cotransporting polypeptide (NTCP), are crucial for the enterohepatic circulation of bile acids. Our objective was to develop a method for measuring bile acid transporter activity in real time to precisely evaluate rapid changes in their function. We designed a reporter system relying on a novel probe: cholic acid attached to luciferin via a disulfide-containing, self-immolating linker (CA-SS-Luc). Incubation of human embryonic kidney-293 cells coexpressing luciferase and ASBT with different concentrations of CA-SS-Luc (0.01-1 μM) resulted in bioluminescence with an intensity that was concentration- and time-dependent. The bioluminescence measured during incubation with 1 μM CA-SS-Luc was dependent on the levels of ASBT or NTCP expressed in the cells. Coincubation of CA-SS-Luc with natural bile acids enhanced the bioluminescence in a concentration-dependent manner with kinetic parameters for ASBT similar to those previously reported using conventional methods. These findings suggest that this method faithfully assesses ASBT function. Further, incubation with tyrosine phosphatase inhibitor III (PTPIII) led to significantly increased bioluminescence in cells expressing ASBT, consistent with previous studies showing an increase in ASBT function by PTPIII. We then investigated CA-SS-Luc in isolated mouse intestinal epithelial cells. Ileal enterocytes displayed significantly higher luminescence compared with jejunal enterocytes, indicating a transport process mediated by ileal ASBT. In conclusion, we have developed a novel method to monitor the activity of bile acid transporters in real time that has potential applications both for in vitro and in vivo studies. NEW & NOTEWORTHY This article reports the development of a real-time method for measuring the uptake of bile acids using a bioluminescent bile acid-based probe. This method has been validated for measuring uptake via the apical sodium-dependent bile acid transporter and the sodium-taurocholate cotransporting polypeptide in cell culture and ex vivo intestinal models.

Safety and efficacy of elobixibat for chronic constipation: results from a randomised, double-blind, placebo-controlled, phase 3 trial and an open-label, single-arm, phase 3 trial

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.

744 - Medium-Term Efficacy and Long-Term Safety of Ileal Bile Acid Transporter Inhibitor, Elobixibat, in Chronic Constipation

744 - Medium-Term Efficacy and Long-Term Safety of Ileal Bile Acid Transporter Inhibitor, Elobixibat, in Chronic Constipation

Pilot study with IBAT inhibitor A4250 for the treatment of cholestatic pruritus in primary biliary cholangitis

Pruritus is a common complication of cholestatic liver diseases. Inhibition of the ileal bile acid transporter (IBAT/ASBT) may emerge as treatment option. Our aim was to assess tolerability and effect on pruritus of the selective IBAT inhibitor A4250 in patients with primary biliary cholangitis (PBC). Ten patients with PBC and bile acid sequestrant treatment of cholestatic pruritus were after a two-week wash out of the bile acid sequestrant treated with either 0.75 mg (n = 4) or 1.5 mg (n = 5) of A4250 for four weeks. Patients’ pruritus was assessed by Visual Analogue Scale (VAS), 5-D itch scale and the pruritus module of the PBC40 questionnaire. Plasma bile acids and 7α-hydroxy-4-cholesten-3-one were measured by UPLC-MS/MS, plasma fibroblast growth factor 19 by ELISA, and serum autotaxin activity by homemade assay. All nine patients exposed to A4250 reported a remarkable improvement in pruritus, until none or mild according to 5-D itch, VAS and PBC40 pruritus. Five patients finished the study prematurely due to abdominal pain (5/5) and diarrhoea (4/5). The high incidence of probably bile acid malabsorption-related diarrhoea and abdominal pain in the bile acid sequestrant pre-treated population indicates that the start dose of A4250 may have been too high for adult patients.

SAT-060 - Correlation of autotaxin levels, serum bile acids, and pruritus in a multiple-dose, open-label, multinational study of the ileal bile acid transport inhibitor A4250

SAT-060 - Correlation of autotaxin levels, serum bile acids, and pruritus in a multiple-dose, open-label, multinational study of the ileal bile acid transport inhibitor A4250

A randomised, double-blind, placebo-controlled phase 1 study of the safety, tolerability and pharmacodynamics of volixibat in overweight and obese but otherwise healthy adults: implications for treatment of non-alcoholic steatohepatitis

BackgroundAccumulation of toxic free cholesterol in hepatocytes may cause hepatic inflammation and fibrosis. Volixibat inhibits bile acid reuptake via the apical sodium bile acid transporter located on the luminal surface of the ileum. The resulting increase in bile acid synthesis from cholesterol could be beneficial in patients with non-alcoholic steatohepatitis. This adaptive dose-finding study investigated the safety, tolerability, pharmacodynamics, and pharmacokinetics of volixibat.MethodsOverweight and obese adults were randomised 3:1 to double-blind volixibat or placebo, respectively, for 12 days. Volixibat was initiated at a once-daily dose of 20 mg, 40 mg or 80 mg. Based on the assessment of predefined safety events, volixibat dosing was either escalated or reduced. Other dose regimens (titrations and twice-daily dosing) were also evaluated. Assessments included safety, tolerability, stool hardness, faecal bile acid (FBA) excretion, and serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and lipids.ResultsAll 84 randomised participants (volixibat, 63; placebo, 21) completed the study, with no serious adverse events at doses of up to 80 mg per day (maximum assessed dose). The median number of daily bowel evacuations increased from 1 (range 0–4) to 2 (0–8) during volixibat treatment, and stool was looser with volixibat than placebo. Volixibat was minimally absorbed; serum levels were rarely quantifiable at any dose or sampling time point, thereby precluding pharmacokinetic analyses. Mean daily FBA excretion was 930.61 μmol (standard deviation [SD] 468.965) with volixibat and 224.75 μmol (195.403) with placebo; effects were maximal at volixibat doses ≥20 mg/day. Mean serum C4 concentrations at day 12 were 98.767 ng/mL (standard deviation, 61.5841) with volixibat and 16.497 ng/mL (12.9150) with placebo. Total and low-density lipoprotein cholesterol levels decreased in the volixibat group, with median changes of − 0.70 mmol/L (range − 2.8 to 0.4) and − 0.6990 mmol/L (− 3.341 to 0.570), respectively.ConclusionsThis study indicates that maximal inhibition of bile acid reabsorption, as assessed by FBA excretion, occurs at volixibat doses of ≥20 mg/day in obese and overweight adults, without appreciable change in gastrointestinal tolerability. These findings guided dose selection for an ongoing phase 2 study in patients with non-alcoholic steatohepatitis.Trial registrationClinicalTrials.gov identifier: NCT02287779 (registration first received 6 November 2014).