Crofelemer

Abstract: Over half of patients with human immunodeficiency virus (HIV) experience diarrhea that contributes negatively to quality of life and adherence to antiretroviral therapy (ART). Opportunistic infectious agents that cause diarrhea in patients with HIV span the array of protozoa, fungi, viruses, and bacteria. With global use of ART, the incidence of diarrhea because of opportunistic infections has decreased; however, the incidence of noninfectious diarrhea has increased. The etiology of noninfectious diarrhea in patients with HIV is multifactorial and includes ART-associated diarrhea and gastrointestinal damage related to HIV infection (i.e., HIV enteropathy). A basic algorithm for the diagnosis of diarrhea in patients with HIV includes physical examination, a review of medical history, assessment of HIV viral load and CD4+ T cell count, stool microbiologic assessment, and endoscopic evaluation, if needed. For patients with negative diagnostic results, the diagnosis of noninfectious diarrhea may be considered. Pharmacologic options for the treatment of noninfectious diarrhea are primarily supportive; however, the use of many unapproved agents is based on unstudied and anecdotal information. In addition, these agents can be associated with treatment-limiting adverse events (AEs), such as drug–drug interactions with ART regimens, abuse liability, and additional gastrointestinal AEs. Currently, crofelemer, an antisecretory agent, is the only therapy approved in the USA for the symptomatic relief of noninfectious diarrhea in patients with HIV on ART.

Abstract: Secretory diarrhea is a leading cause of morbidity and mortality worldwide. Crofelemer is a first-in-class antidiarrheal agent that simultaneously targets two distinct channels, the cystic fibrosis conductance regulator and calcium-activated chloride channel, responsible for chloride and fluid secretion in the GI tract. Crofelemer is a novel compound extracted from the stem bark latex of the Croton lechleri tree found in the western Amazonian region of South America. There is little to no systemic absorption of crofelemer when given orally and studies have shown minimal toxicity beyond mild gastrointestinal effects. In studies in diarrheal illness associated with primarily a secretory component, such as cholera, travelers’ diarrhea and acute infectious diarrhea, crofelemer has shown improvements in stool consistency and duration of symptoms. Less clear, but interesting, results have been observed in other diarrheal diseases associated with a mixed pathology, including diarrhea in patients with HIV and dia...

Abstract: The present invention provides methods for treating constipation-predominant irritable bowel syndrome comprising administering to a patient in need thereof, a polymeric proanthocyanidin composition from a Croton species or Calophyllum species in an amount sufficient to treat constipation-predominant irritable bowel syndrome (c-IBS). Treatment of c-IBS includes the treatment of the constipation component of c-IBS as well as the pain and abdominal discomfort associated with c-IBS. In one embodiment, the polymeric proanthocyanidin compound is crofelemer. The present invention in an alternative embodiment also provides methods for treating alternating constipation-predominant/diarrhea-predominant irritable bowel syndrome.

Abstract: Background: HIV-associated diarrhea remains a significant concern with limited treatment options. Objective: To determine the optimal dose, efficacy, and safety of crofelemer for noninfectious diarrhea. Methods: This randomized, double-blind, phase 3 trial used a 2-stage design. Both stages included 2-week screening, 4-week placebo-controlled treatment, and 20-week placebo-free (open-label) extension phases. In stage I, 196 HIV-seropositive patients with chronic diarrhea were randomized to crofelemer 125 mg, 250 mg, or 500 mg or placebo twice daily. Using a prospective analysis, the 125-mg twice-daily dose was selected for stage II. In stage II, 180 new patients were randomized to crofelemer 125 mg twice daily or placebo for 4 weeks. Primary efficacy analysis was the percentage of patients (stages I/II combined) who achieved clinical response (defined as ≤2 watery stools/week during ≥2 of 4 weeks). During the placebo-free extension phase, response (≤2 watery stools) was assessed weekly. Results: S...