Irritable Bowel Syndrome With Constipation Research Articles

Combined MRI, high-resolution manometry and a randomised trial of bisacodyl versus hyoscine show the significance of an enlarged colon in constipation: the RECLAIM study

BackgroundColonic motility in constipation can be assessed non-invasively using MRI.ObjectiveTo compare MRI with high-resolution colonic manometry (HRCM) for predicting treatment response.DesignPart 1: 44 healthy volunteers (HVs), 43 patients with irritable...

Efficacy and safety of linaclotide in treatment-resistant chronic constipation: A multicenter, open-label study.

This study aimed to evaluate the efficacy and safety of linaclotide in patients with chronic constipation (CC) or irritable bowel syndrome with constipation (IBS-C) who did not respond to treatment with magnesium oxide (MgO). This study was designed as a multicenter, open-label, single-arm, exploratory study. Patients with CC or IBS-C who took MgO and those meeting the medication initiation criteria were administered linaclotide at a daily dosage of 500 μg for 12 weeks. The primary endpoint was a change in the Japanese version of the Patient Assessment of Constipation Quality of Life (JPAC-QOL) score from baseline, which was evaluated by using a paired t-test. The patients' mean age (± standard deviation) was 67.6 ± 13.82 years. The full analysis set included 61 patients. The JPAC-QOL total score was 1.60 at baseline and 0.70 at 12 weeks, with a significant mean change of -0.89 ± 0.721 (p < 0.001). Several secondary endpoints also showed improvement. The frequency of spontaneous bowel movement (SBM) and complete SBM increased by 2.70 ± 7.254 (p < 0.01) and 2.81 ± 5.254 times, respectively (p < 0.001). The Bristol Stool Form Scale, abdominal bloating severity, and straining severity scores improved by 1.33 ± 1.274 (p < 0.001), -0.16 ± 0.563 (p < 0.05), and -0.46 ± 0.795 (p < 0.001) points, respectively. The safety analysis set included 65 patients, 7 of whom had diarrhea, which improved with dose reduction and drug withdrawal. The study was conducted in an older adult population, similar to real clinical practice. Linaclotide may be an option for treating CC that shows an inadequate response to conventional therapy.

S799 Plecanatide Is Efficacious in Patients With Irritable Bowel Syndrome With Constipation (IBS-C) and Bloating: Evaluation Using Trisymptom Composite Endpoints

S799 Plecanatide Is Efficacious in Patients With Irritable Bowel Syndrome With Constipation (IBS-C) and Bloating: Evaluation Using Trisymptom Composite Endpoints

An Exploratory Study on Integrative Management of Irritable Bowel Syndrome with Constipation (IBS-C)

Irritable Bowel Syndrome (IBS) was complicated disorder that results in pain and change in bowel habits. The major contributing factors to the onset and detoriation include stress and gastrointestinal problem. The women between 20 to 40 years were most commonly involved. The prevalence varies among countries that was affected by diet and diagnostic criteria. Objective: Compairing the efficacy of Mebeverine, Polyethylene Glycol with the combination therapy of Mebeverine and Polyethylene Glycol in Irritable Bowel Syndrome associated with Constipation. Methods: The comparative analytical study was conducted at the National Medical Centre, Karachi, and approved by the Ethical Review Committee of Bahria University Health Science Campus. Participants aged 15-50 with IBS were selected to reflect the target population. Observational data were collected based on the treatments they naturally received: Mebeverine, Polyethylene glycol, or a combination. Pain and constipation status were recorded at baseline (day 0) and after 24 days, analyzing the effectiveness of the treatments as they were administered in routine care settings. Results: The demographic data mentioned comparable age, weight, height, and gender distribution across the three groups. Constipation and pain status before and after varied considerably across the investigation time. There was substantial improvements by day 24 from the baseline in the combination therapy. Conclusions: The combination of Mebeverine and Polyethylene glycol reveals in managing IBS, with prominent improvements in constipation severity over the research duration. This highlights the importance of multimodal treatment methods in addressing the varied symptoms of IBS and enhancing the quality of life.

Effect of Lacticaseibacillus rhamnosus IDCC 3201 on irritable bowel syndrome with constipation: a randomized, double-blind, and placebo-controlled trial

Irritable bowel syndrome is a chronic disorder affecting the gastrointestinal tract, negatively impacting patients’ quality of life. Here, we aimed to evaluate the effects of Lacticaseibacillus rhamnosus IDCC 3201 (RH 3201) on irritable bowel syndrome with constipation (IBS-C). In this randomised, double-blind, placebo-controlled trial, a total of 30 subjects with IBS-C were randomly assigned (1:1) to receive 8 weeks of probiotics administration or placebo. Concerning bowel activities, both irritant bowel movements and discomfort caused by constipation showed significant improvement with RH 3201 at 8 weeks. Symptoms including severity of abdominal bloating, frequency of abdominal bloating, and satisfaction of bowel habits based on the irritable bowel syndrome-severity scoring system also ameliorated in the probiotic group. Analysis of the fecal microbiome revealed that the abundance of Bacteroides cellulosilyticus and Akkermansia muciniphila was higher during the period of RH 3201 administration compared to the placebo. Untargeted metabolome analysis further suggested a correlation between specific metabolites, such as N-acetylornithine, xanthine, and 3-phenylpropionic acid, and the improvement of clinical symptoms. These results indicate that RH 3201 was effective in ameliorating IBS-C, potentially by enriching beneficial microbes and associated metabolites in the gut environment.

Burden of illness and treatment attitudes among participants meeting Rome IV criteria for irritable bowel syndrome: A nationwide survey in the United States.

Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction characterized by abdominal pain and altered bowel habits, with patient-perceived dissatisfaction of treatment symptom control. We assessed disease burden, satisfaction with medication use, and impact on activities, in participants with IBS with constipation (IBS-C) and diarrhea (IBS-D). This study assessed data from a large, United States survey of adults querying demographics, comorbid conditions, quality of life, medication use, satisfaction with symptom control, and work productivity. Participants were grouped into the IBS-C or IBS-D cohort if they met Rome IV criteria, with controls matched 1:1 according to age, sex, race, region, and Charlson Comorbidity Index score. All data were self-reported. Nine hundred and ten participants with IBS-C and 669 with IBS-D were matched to controls. The most reported symptoms were abdominal discomfort for IBS-C and abdominal pain and abdominal discomfort for IBS-D. Among the IBS-C and IBS-D cohorts, 74.2% and 65.9%, respectively, took prescription and/or over-the-counter medication for their symptoms. Respondents were more dissatisfied than satisfied with control of their symptoms. Respondents taking prescription medication(s) with or without over-the-counter medication(s) reported better symptom control than respondents only taking over-the-counter medications (p < 0.001). There was significantly higher mean presenteeism, work productivity loss, and daily activity impairment (p < 0.001 for all) in respondents with IBS compared with controls. This study provides insight into respondents' experiences of IBS symptoms, including the impact on daily activity, as well as satisfaction with control of symptoms and prescription and over-the-counter medications.

A diet low in fermentable oligo-, di-, monosaccharides and polyols improves abdominal and overall symptoms in persons with all subtypes of irritable bowel syndrome.

A diet low in fermentable oligo-, di-, monosaccharides and polyols (LFD) improves symptoms in patients with irritable bowel syndrome (IBS). Previous studies have focused on patients with IBS and diarrhea (IBS-D). It is unclear whether LFD is effective for IBS with constipation (IBS-C) or IBS with mixed bowel habits (IBS-M). This open-label, real-world study evaluates the relative effectiveness of the LFD among IBS subtypes. This study analyzes data from a service that provides low-FODMAP meals to individuals with IBS. Participants met with a registered dietitian and completed the IBS symptom severity survey (IBS-SSS) before and after undergoing a 2-4-week period of FODMAP restriction. The primary endpoint was the proportion of participants with ≥50-point decrease in IBS-SSS between the three IBS subtypes. After FODMAP restriction, 90% of participants with IBS-D, 75% with IBS-C, and 84% with IBS-M met the primary endpoint (p = 0.045). Similar improvement was seen for a 100-point decrease, but the difference between IBS subtypes was not significant (p = 0.46). After FODMAP restriction, all groups had statistically significant improvement in total IBS-SSS as well as individual symptom categories. Improvement in IBS-SSS subcategories was similar among the groups except for the categories of bloating severity (IBS-M had greatest improvement) and bowel movement satisfaction (IBS-C had less improvement). Though the proportion of responders was highest for IBS-D and lowest for IBS-C, the LFD led to robust improvement in overall symptoms in all IBS subtypes. Key individual symptoms also showed significant improvements in all IBS subtypes.

Plecanatide Improves Abdominal Bloating and Bowel Symptoms of Irritable Bowel Syndrome with Constipation.

Bloating is a bothersome symptom in irritable bowel syndrome with constipation (IBS-C). To evaluate plecanatide efficacy in patients with IBS-C stratified by bloating intensity. Pooled phase 3 data (2 randomized, controlled IBS-C trials) from adults treated with plecanatide 3mg or placebo for 12weeks were analyzed. Patients were stratified post-hoc by baseline bloating severity (11-point scale: mild [≤ 5] and moderate-to-severe [> 5]). Assessments included change from baseline in bloating, abdominal pain, and complete spontaneous bowel movement (CSBM) frequency. Abdominal pain and bloating composite responders were defined as patients with ≥ 30% improvement from baseline in both bloating and abdominal pain at Week 12. At baseline, 1104/1436 patients with IBS-C (76.9%) reported moderate-to-severe bloating. In the moderate-to-severe bloating subgroup, plecanatide significantly reduced bloating severity versus placebo (least-squares mean change [LSMC]: -1.7 vs -1.3; P = 0.002), reduced abdominal pain (-1.7 vs -1.3; P = 0.006), and increased CSBM frequency (1.4 vs 0.8; P < 0.0001). In the mild bloating subgroup, significant improvements were observed with plecanatide versus placebo for abdominal pain (LSMC: -1.3 vs -1.0; P = 0.046) and CSBM frequency (2.0 vs 1.2; P = 0.003) but not bloating (-0.9 vs -0.8; P = 0.28). A significantly greater percentage of patients were abdominal pain and bloating composite responders with plecanatide versus placebo (moderate-to-severe bloating: 33.6% vs 26.8% [P = 0.02]; mild bloating: 38.4% vs 27.2% [P = 0.03]). Plecanatide treatment improved IBS-C abdominal and bowel symptoms, including in those who present with moderate-to-severe bloating.

An Overview of the Effects of Tenapanor on Visceral Hypersensitivity in the Treatment of Irritable Bowel Syndrome with Constipation.

Patients with irritable bowel syndrome with constipation (IBS-C) experience persistent abdominal pain, a common symptom leading to greater healthcare utilization and reports of treatment non-response. Clinically significant improvements in abdominal pain were observed in clinical trials of tenapanor, a first-in-class inhibitor of sodium/hydrogen exchanger isoform 3 (NHE3), for the treatment of IBS-C in adults. This narrative review reports the current knowledge about visceral hypersensitivity as a mechanism for abdominal pain in patients with IBS-C and explores the published evidence for hypothesized mechanisms by which tenapanor may reduce visceral hypersensitivity leading to the observed clinical response of decreased abdominal pain. Abdominal pain is experienced through activation and signaling of nociceptive dorsal root ganglia that innervate the gut. These sensory afferent neurons may become hypersensitized through signaling of transient receptor potential cation channel subfamily V member 1 (TRPV1), resulting in reduced action potential thresholds. TRPV1 signaling is also a key component of the proinflammatory cascade involving mast cell responses to macromolecule exposure following permeation through the intestinal epithelium. Indirect evidence of this pathway is supported by observations of higher pain in association with increased intestinal permeability in patients with IBS. Tenapanor reduces intestinal sodium absorption, leading to increased water retention in the intestinal lumen, thereby improving gastrointestinal motility. In animal models of visceral hypersensitivity, tenapanor normalized visceromotor responses and normalized TRPV1-mediated nociceptive signaling. By improving gastrointestinal motility, decreasing intestinal permeability and inflammation, and normalizing nociception through decreased TRPV1 signaling, tenapanor may reduce visceral hypersensitivity, leading to less abdominal pain in patients with IBS-C. Therapies that have demonstrated effects on visceral hypersensitivity may be the future direction for meaningful abdominal pain relief for patients with IBS-C.

Tenapanor (Xphozah) for hyperphosphatemia in chronic kidney disease.

The FDA has approved the sodium/hydrogen exchanger 3 (NHE3) inhibitor tenapanor (Xphozah – Ardelyx) to reduce serum phosphorus in adults with chronic kidney disease (CKD) on dialysis as add-on therapy when phosphate binders are ineffective or as monotherapy when phosphate binders cannot be tolerated. Tenapanor is the first NHE3 inhibitor to be approved in the US for hyperphosphatemia. It was previously approved as Ibsrela to treat irritable bowel syndrome with constipation (IBS-C).

Clinical features, anxiety and depression among patients with irritable bowel syndrome with constipation and Hashimoto’s thyroiditis with hypothyroidism

Clinical features, anxiety and depression among patients with irritable bowel syndrome with constipation and Hashimoto’s thyroiditis with hypothyroidism

A Narrative Review on the Viability of Osteopathic Manipulative Medicine in Treating Irritable Bowel Syndrome With Constipation (IBS-C).

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by chronic abdominal pain and alterations in bowel habits, with global prevalence.The etiology of the disease is likely multifactorial; however, autonomic nervous system (ANS) dysfunction and immune-mediated inflammation may contribute the most to the hallmark symptoms of abdominal pain and altered motility of the gut. Current pharmacological therapies operate to modulate intestinal transit, alter the composition of the gut flora and control pain. Non-pharmacological approaches include dietary changes, increased physical activity, or fecal microbiota transplants. None of these therapies can modulate ANS dysfunction or impact the underlying inflammation that is likely perpetuating the symptoms of IBS. Osteopathic Manipulative Medicine (OMM) is a clinical approach focused on physical manipulation of the body's soft tissues to correct somatic dysfunctions. OMM can directly target the pathophysiology of IBS through many approaches such as ANS modulation and lymphatic techniques to modify the inflammatory mechanisms within the body. Particular OMM techniques of use are lymphatic manipulation, myofascial release, sympathetic ganglia treatment, sacral rocking, counterstrain, and viscerosomatic treatment. The aim of this study is to identify OMM treatments that can be used to potentially reduce the inflammation and ANS dysfunction associated with IBS symptoms, thereby providing a new non-pharmacological targeted approach for treating the disease.

Abdominal Symptom Improvement During Clinical Trials of Tenapanor in Patients With Irritable Bowel Syndrome With Constipation: A Post Hoc Analysis.

This post hoc analysis evaluated the efficacy of tenapanor on abdominal symptoms in patients with irritable bowel syndrome with constipation. Abdominal symptoms assessed included pain, discomfort, bloating, cramping, and fullness. The abdominal symptom data were pooled from 3 randomized controlled trials (NCT01923428, T3MPO-1 [NCT02621892], and T3MPO-2 [NCT02686138]). Weekly scores were calculated for each abdominal symptom, and the Abdominal Score (AS) was derived as the average of weekly scores for abdominal pain, discomfort, and bloating. The overall change from baseline during the 12 weeks was assessed for each symptom weekly score and the AS. The AS 6/12-week and 9/12-week response rates (AS improvement of ≥2 points for ≥6/12- or ≥9/12-week) were also evaluated. The association of weekly AS response status (reduction of ≥30%) with weekly complete spontaneous bowel movement (CSBM) status (=0 and >0) was assessed. Among 1,372 patients (684 tenapanor [50 mg twice a day] and 688 placebo), the least squares mean change from baseline in AS was -2.66 for tenapanor vs -2.09 for placebo ( P < 0.0001). The 6/12-week AS response rate was 44.4% for tenapanor vs 32.4% for placebo ( P < 0.0001), and for 9/12-week AS, 30.6% for tenapanor vs 20.5% for placebo ( P < 0.0001). A significant association between weekly CSBM status and weekly AS response status was observed each week ( P < 0.0001), with a greater proportion achieving an AS reduction in patients with >0 CSBMs in a week. Tenapanor significantly reduced abdominal symptoms in patients with irritable bowel syndrome with constipation, particularly pain, discomfort, and bloating measured by AS, compared with placebo.

Relationship Between Colonic Transit Response to Eating With Self-reported Constipation Severity in Constipated Patients According to the Phenotype.

Eating is the major synchronizer of gastrointestinal motility and secretions. The present study aims to evaluate the interplay between self-perceived constipation severity (CS) and colonic response to eating in constipated patients according to the phenotype. We included 387 consecutive outpatients complaining of Rome IV chronic idiopathic constipation. Likert scales for CS, abdominal pain severity, bloating severity, depression and anxiety assessment, total and segmental colonic transit time (CTT), and colonic transit response to eating (CTRE) were performed in all patients. Of the 387 patients included (49.7 ± 16.4 years), 320 (83%) were female, 203 had irritable bowel syndrome with constipation (IBS-C), 184 as functional constipation (FC), and 283 had defecation disorders (DD). The female gender was characterized by increased bloating severity (P = 0.011) and decreased Bristol stool form (P = 0.002). In IBS-C and FC patients, CS was related with bloating severity (P < 0.001 in both groups) and total CTT (P = 0.007 in IBS-constipation, P = 0.040 in FC). In IBS-C patients, CS was also associated with abdominal pain severity (P = 0.003) and Bristol stool form (P = 0.004). In contrast, in FC, CS was only related to left CTRE (P = 0.006), and in patients with DD, CS was associated with total CTT (P < 0.001) and left CTRE (P = 0.002). Colonic transit response to eating was not associated to CS in IBS-C patients, but left CTRE was associated with constipation severity in FC and DD patients.

The gut microbiota participates in the effect of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C): a multicenter, prospective, pre-post study

BackgroundInterindividual variation characterizes the relief experienced by constipation-predominant irritable bowel syndrome (IBS-C) patients following linaclotide treatment. Complex bidirectional interactions occur between the gut microbiota and various clinical drugs. To date, no established evidence has elucidated the interactions between the gut microbiota and linaclotide. We aimed to explore the impact of linaclotide on the gut microbiota and identify critical bacterial genera that might participate in linaclotide efficacy.MethodsIBS-C patients were administered a daily linaclotide dose of 290 µg over six weeks, and their symptoms were then recorded during a four-week posttreatment observational period. Pre- and posttreatment fecal samples were collected for 16S rRNA sequencing to assess alterations in the gut microbiota composition. Additionally, targeted metabolomics analysis was performed for the measurement of short-chain fatty acid (SCFA) concentrations.ResultsApproximately 43.3% of patients met the FDA responder endpoint after taking linaclotide for 6 weeks, and 85% of patients reported some relief from abdominal pain and constipation. Linaclotide considerably modified the gut microbiome and SCFA metabolism. Notably, the higher efficacy of linaclotide was associated with enrichment of the Blautia genus, and the abundance of Blautia after linaclotide treatment was higher than that in healthy volunteers. Intriguingly, a positive correlation was found for the Blautia abundance and SCFA concentrations with improvements in clinical symptoms among IBS-C patients.ConclusionThe gut microbiota, especially the genus Blautia, may serve as a significant predictive microbe for symptom relief in IBS-C patients receiving linaclotide treatment.Trial registration: This trial was registered with the Chinese Clinical Trial Registry (Chictr.org.cn, ChiCTR1900027934).

NHE3 inhibitor tenapanor maintains intestinal barrier function, decreases visceral hypersensitivity, and attenuates TRPV1 signaling in colonic sensory neurons.

The pathogenesis of irritable bowel syndrome (IBS) is multifactorial, characterized in part by increased intestinal permeability, and visceral hypersensitivity. Increased permeability is associated with IBS severity and abdominal pain. Tenapanor is FDA-approved for the treatment of IBS with constipation (IBS-C) and has demonstrated improvements in bowel motility and a reduction in IBS-related pain; however, the mechanism by which tenapanor mediates these functions remains unclear. Here, the effects of tenapanor on colonic pain signaling and intestinal permeability were assessed through behavioral, electrophysiological, and cell culture experiments. Intestinal motility studies in rats and humans demonstrated that tenapanor increased luminal sodium and water retention and gastrointestinal transit versus placebo. A significantly reduced visceral motor reflex (VMR) to colonic distension was observed with tenapanor treatment versus vehicle in two rat models of visceral hypersensitivity (neonatal acetic acid sensitization and partial restraint stress; both P < 0.05), returning VMR responses to that of nonsensitized controls. Whole cell voltage patch-clamp recordings of retrogradely labeled colonic dorsal root ganglia (DRG) neurons from sensitized rats found that tenapanor significantly reduced DRG neuron hyperexcitability to capsaicin versus vehicle (P < 0.05), an effect not mediated by epithelial cell secretions. Tenapanor also attenuated increases in intestinal permeability in human colon monolayer cultures caused by incubation with proinflammatory cytokines (P < 0.001) or fecal supernatants from patients with IBS-C (P < 0.005). These results support a model in which tenapanor reduces IBS-related pain by strengthening the intestinal barrier, thereby decreasing permeability to macromolecules and antigens and reducing DRG-mediated pain signaling.NEW & NOTEWORTHY A series of nonclinical experiments support the theory that tenapanor inhibits IBS-C-related pain by strengthening the intestinal barrier. Tenapanor treatment reduced visceral motor responses to nonsensitized levels in two rat models of hypersensitivity and reduced responses to capsaicin in sensitized colonic nociceptive dorsal root ganglia neurons. Intestinal permeability experiments in human colon monolayer cultures found that tenapanor attenuates increases in permeability induced by either inflammatory cytokines or fecal supernatants from patients with IBS-C.

Intestinal Permeability, Irritable Bowel Syndrome with Constipation, and the Role of Sodium-Hydrogen Exchanger Isoform 3 (NHE3).

Increased intestinal permeability has been identified as one of the many pathophysiological factors associated with the development of irritable bowel syndrome (IBS), a common disorder of gut-brain interaction. The layer of epithelial cells that lines the intestine is permeable to a limited degree, and the amount of paracellular permeability is tightly controlled to enable the absorption of ions, nutrients, and water from the lumen. Increased intestinal permeability to macromolecules can be triggered by a variety of insults, including infections, toxins from food poisoning, or allergens, which in turn cause an inflammatory response and are associated with abdominal pain in patients with IBS. This review article discusses increased intestinal permeability in IBS, focusing on IBS with constipation (IBS-C) through the lens of a patient case with a reported prior diagnosis of "leaky gut syndrome" upon initial contact with a gastrointestinal specialist. We review advantages and disadvantages of several methods of measuring intestinal permeability in patients and discuss when measuring intestinal permeability is appropriate in the therapeutic journey of patients with IBS-C. Furthermore, we discuss a possible mechanism of restoring the intestinal barrier to its healthy state through altering intracellular pH by inhibiting sodium-hydrogen exchanger isoform 3 (NHE3). Tenapanor is a minimally absorbed, small-molecule inhibitor of NHE3 that has been approved by the US Food and Drug Administration for the treatment of IBS-C in adults. Preclinical studies showed that tenapanor may restore the intestinal barrier in IBS-C by affecting the conformation of tight junction proteins via NHE3 inhibition to block the paracellular transport of macromolecules from the intestinal lumen. Testing for increased permeability in patients with IBS-C who experience abdominal pain may help inform the choice of therapeutics and alter patients' misconceptions about "leaky gut syndrome".

Long-term safety of tenapanor in people with irritable bowel syndrome with constipation from the T3MPO-3 study: plain language summary of publication.

This document provides a short summary of the T3MPO-3 study, which was published in Neurogastroenterology and Motility in September 2023. At the end of this summary, there are links to websites where you can find more information about this study. Tenapanor (IBSRELA®) is a newly available medicine in the United States. It is used to treat irritable bowel syndrome with constipation (IBS-C) in people aged 18 years and older. In 2 large clinical trials, tenapanor was shown to improve the symptoms of IBS-C. People with IBS-C often need to take long-term medicines to keep their symptoms under control. As a result, this study, called T3MPO-3, was undertaken to investigate whether there are any possible side effects associated with the long-term use of tenapanor in adults with IBS-C. There were 312 people who had taken part in either of the original 2 trials and took part in this study, with 90 receiving tenapanor for at least 1 year. Loose or watery stool (diarrhea) was the most common side effect, and most cases were mild or moderate. No people died in any of these studies.

Review of the Patient Burden and Therapeutic Landscape of Irritable Bowel Syndrome with Constipation in the United States.

Irritable bowel syndrome (IBS) is a common disorder of the gut-brain axis. IBS with constipation (IBS-C) accounts for approximately one-third of IBS cases and is associated with substantial burden of illness and decreased quality of life. This narrative review provides an overview of the current and upcoming treatment options and disease management for IBS-C from a US perspective and discusses the importance of the relationship between patient and health care provider in diagnosis and treatment. A positive diagnostic strategy for IBS-C is recommended, based on clinical history, physical examination, and minimal laboratory tests. An effective communication strategy between patients and health care professionals is essential to ensure early diagnosis and reduce both health care costs and overall disease burden. Treatment typically begins with lifestyle interventions and nonpharmacologic options, such as dietary interventions, fiber supplements, and osmotic laxatives. In patients with inadequate response to these therapies, 4 currently available therapies (lubiprostone, linaclotide, plecanatide, and tenapanor) approved by the US Food and Drug Administration may relieve IBS-C symptoms. These agents are generally well tolerated and efficacious in improving IBS-C symptoms, including constipation and abdominal pain. In patients with persistent abdominal pain and/or psychological symptoms, brain-gut behavioral therapy or neuromodulator therapy may be beneficial.

Physiologically Based Biopharmaceutics Model (PBBM) of Minimally Absorbed Locally Acting Drugs in the Gastrointestinal Tract-Case Study: Tenapanor.

A physiologically based biopharmaceutics model (PBBM) was developed to predict stool and urine sodium content in response to tenapanor administration in healthy subjects. Tenapanor is a minimally absorbed small molecule that inhibits the sodium/hydrogen isoform 3 exchanger (NHE3). It is used to treat irritable bowel syndrome with constipation (IBS-C). Its mode of action in the gastrointestinal tract reduces the uptake of sodium, resulting in an increase in water secretion in the intestinal lumen and accelerating intestinal transit time. The strategy employed was to perform drug-drug interaction (DDI) modelling between sodium and tenapanor, with sodium as the "victim" administered as part of daily food intake and tenapanor as the "perpetrator" altering sodium absorption. Food effect was modelled, including meal-induced NHE3 activity using sodium as an inducer by normalising the induction kinetics of butyrate to sodium equivalents. The presented model successfully predicted both urine and stool sodium content in response to tenapanor dosed in healthy subjects (within 1.25-fold error) and provided insight into the clinical observations of tenapanor dosing time relative to meal ingestion. The PBBM model was applied retrospectively to assess the impact of different forms of tenapanor (free base vs. HCl salt) on its pharmacodynamic (PD) effect. The developed modelling strategy can be effectively adopted to increase confidence in using PBBM models for the prediction of the in vivo behaviour of minimally absorbed, locally acting drugs in the gastrointestinal tract, when other approaches (e.g., biomarkers or PD data) are not available.