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Linaclotide: A new drug for the treatment of chronic constipation and irritable bowel syndrome with constipation.

ABSTRACT: Linaclotide is the first member of a novel class of drugs to be extensively evaluated for the treatment of chronic constipation (CC) and irritable bowel syndrome with constipation (IBS-C).To provide a comprehensive overview of the current state of knowledge on linaclotide, its pharmacological properties, mode of action and efficacy in clinical trials to date.We conducted a systematic review of the literature.The survey revealed that linaclotide is a minimally absorbed, 14-amino acid peptide which acts in the intestinal lumen on guanylate cyclase-C (GC-C). This results in generation of cyclic guanosine monophosphate (cGMP), which stimulates chloride secretion, resulting in increased luminal fluid secretion and an acceleration of intestinal transit. In animal models, linaclotide also decreased visceral hypersensitivity. Linaclotide softened stool and increased transit in CC and in IBS-C. Phase II and phase III clinical studies established efficacy of linaclotide in CC (linaclotide 145?µg daily approved in the United States for CC) and in IBS-C (linaclotide 290?µg daily US Food and Drug Administration-approved for IBS-C, with favourable recommendation for the European Medicines Agency Committee for Medicinal Products for Human Use (CHMP). Linaclotide showed a favourable safety profile, and the main treatment-emerging adverse event was diarrhea, leading to discontinuation rates of up to 5%. Linaclotide is an important addition to the therapeutic possibilities for treating IBS-C and CC.

SUBMITTER: Corsetti M

PROVIDER: S-EPMC4040778 | biostudies-other | 2013 Feb

REPOSITORIES: biostudies-other

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Linaclotide: A new drug for the treatment of chronic constipation and irritable bowel syndrome with constipation.

Corsetti Maura M Tack Jan J

United European gastroenterology journal 20130201 1

<h4>Introduction</h4>Linaclotide is the first member of a novel class of drugs to be extensively evaluated for the treatment of chronic constipation (CC) and irritable bowel syndrome with constipation (IBS-C).<h4>Aim</h4>To provide a comprehensive overview of the current state of knowledge on linaclotide, its pharmacological properties, mode of action and efficacy in clinical trials to date.<h4>Methods</h4>We conducted a systematic review of the literature.<h4>Results</h4>The survey revealed tha ...[more]

PMID: 24917937

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Project description:IntroductionTo inform the patient-centered discussion regarding comparative outcomes with irritable bowel syndrome/chronic idiopathic constipation pharmacotherapy, we evaluated reasons and timing of discontinuation of FDA-approved pharmacotherapy for irritable bowel syndrome and chronic idiopathic constipation in a large observational real-world cohort.MethodsWe identified patients initiating lubiprostone or linaclotide within the University of Michigan Electronic Medical Record (2012-2016). Medication start and stop dates were determined in manual chart review including detailed review of all documentation including office notes and telephone encounters. A Cox model was constructed to predict the hazard of discontinuation.ResultsOn multivariate analysis of 1,612 patients, linaclotide users had a lower risk of discontinuing therapy than lubiprostone users for any reason (hazard ratio [HR] = 0.6, 95% confidence interval [CI] 0.5-0.8). At 3 and 12 months, the overall discontinuation rates were 23% and 43% for lubiprostone compared with 14% and 24% for linaclotide. Over the first year of therapy, more than half of discontinuations due to intolerance occurred in the first 3 months for both drugs. Linaclotide users were more likely to discontinue due to intolerance (HR = 1.6 [95% CI, 1.2-2.3]) but less likely to discontinue due to insufficient efficacy of therapy (HR = 0.5 [95% CI, 0.4-0.8]). IBS diagnosis increased the hazard of discontinuation of lubiprostone relative to linactolide (HR = 1.4, 95% CI, 1.1-1.6). Loss of prescription drug coverage remained a common reason for discontinuation over the first year of therapy.DiscussionIndividuals appear more likely to discontinue lubiprostone than linaclotide overall, but more likely to discontinue linaclotide compared with lubiprostone due to intolerance (mostly diarrhea). Most discontinuations due to intolerance occur in the first 3 months. These results may be useful in individualized treatment selection and enhancing patient knowledge regarding long-term outcomes.

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Linaclotide: A new drug for the treatment of chronic constipation and irritable bowel syndrome with constipation.

Publications

Linaclotide: A new drug for the treatment of chronic constipation and irritable bowel syndrome with constipation.

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