Evaluation of Crofelemer in the Treatment of Diarrhea-Predominant Irritable Bowel Syndrome Patients

Abstract

Background: Crofelemer improves bowel function in several conditions characterized by states of prominent secretory diarrhea. Aim: This double-blind, randomized, placebo-controlled trial evaluated the effects of 3 dose levels of crofelemer in patients with diarrhea-predominant irritable bowel syndrome (D-IBS). Methods: Male and female patients were randomly assigned to receive crofelemer 125, 250 or 500 mg or placebo twice daily for 12 weeks. The primary efficacy measure was a responder for improvement in stool consistency. In addition, abdominal pain- and discomfort-free days, pain and discomfort scores as well as other bowel function parameters (such as stool frequency and consistency, urgency, bloating) were evaluated. Results: Two hundred and forty-two D-IBS patients were randomized. Crofelemer did not produce significant improvement in stool consistency (primary endpoint), stool frequency, urgency or adequate relief. However, female D-IBS patients showed improvement in the proportion of pain- and discomfort-free days during treatment with 500 mg crofelemer: month 1 (crofelemer vs. placebo: 17.7 vs. 10.2%, p = 0.098); month 2 (23.5 vs. 13.3%, p = 0.076); month 3 (26.1 vs. 10.6%, p = 0.0076). No benefit was seen in male D-IBS patients. Crofelemer was well tolerated. Conclusions: Crofelelmer did not produce benefit on bowel function; an increase in the number of pain- and discomfort-free days in female D-IBS patients was seen. Further studies with crofelemer are warranted to evaluate it as a potential visceral analgesic.

Crofelemer, an Antisecretory Antidiarrheal Proanthocyanidin Oligomer Extracted from Croton lechleri, Targets Two Distinct Intestinal Chloride Channels

“…We did not investigate the possibility that crofelemer metabolites formed in the intestine might have additional cellular effects on enterocytes. The dual inhibition of CFTR and CaCC Cl Ϫ channels by crofelemer provides insights into the understanding of its therapeutic effects in the treatment of secretory diarrheal disorders of various etiologies (Holodniy et al, 1999;DiCesare et al, 2002;Mangel and Chaturvedi, 2008), which share the common feature of excessive Cl Ϫ secretion.…”

“…Additional pharmacological studies have shown that crofelemer reduced fluid secretion in cell culture and mouse models (Gabriel et al, 1999). Crofelemer is currently in clinical trials for the treatment of secretory diarrheas associated with acute infections including cholera, chronic diarrhea associated with HIV/AIDS, and diarrhea-predominant irritable bowel syndrome (Holodniy et al, 1999;DiCesare et al, 2002;Mangel and Chaturvedi, 2008). Here, we report that the antisecretory mechanism-of-action of crofelemer involves inhibition of both CFTR and CaCC Cl Ϫ channels at the luminal membrane of enterocytes.…”

Intestinal Secretory Mechanisms and Irritable Bowel Syndrome

“…4 However, in a double-blind, randomized, placebo-controlled trial, crofelemer, a channel chloride blocker of both CFTR and the calcium-activated chloride channels, did not produce a benefit in stool consistency in diarrhea-predominant IBS patients. 5 Second, the possible secretion of colonic mucus…”

Current and Emerging Pharmacotherapeutic Options for Irritable Bowel Syndrome

“…These agents relieve pain and improve diarrhoea in patients with IBS-D [104,105]. Although large RCTs in un-subtyped IBS have not shown asimadoline to improve pain/discomfort as compared with placebo [105], patients with IBD-D experienced significant improvement in adequate relief of IBS pain (47 %) Crofelemer Regulates fluid secretion and water loss due to diarrhoea and normalizes chloride ion and water flow in the GI tract by inhibiting the cAMP-stimulated CFTR chloride ion channel and the CaCC in the luminal membrane Use of crofelemer was evaluated in a double-blind placebo-controlled RCT in 242 patients with IBS-D for 12 weeks [106]. The primary endpoint was a responder for improvement in stool consistency.…”

“…Another treatment for IBS-D is the drug crofelemer, which has been shown to normalize chloride ion channel and water flow in the GI tract and therefore regulates fluid secretion and water loss by inhibiting ion channels in the luminal membrane [106]. However, crofelemer did not improve bowel frequency when compared with placebo, although an improvement in pain/discomfort was seen in females with IBS-D.…”