1.Cost-effectiveness of linaclotide compared to antidepressants in the treatment of irritable bowel syndrome with constipation in Scotland
Mark Fisher • Andrew Walker • Meritxell Falques. Eur J Health Econ
Linaclotide is indicated as a continuous treatment provided the patient does not discontinue due to lack of efficacy or adverse events. Clinical efficacy data were available up to 26 weeks based upon the phase III clinical trials and therefore required extrapolation for the purposes of the cost-effectiveness model. In order to capture the important differences in costs and outcomes for IBS-C treatment, with moderate data extrapolation, a 5-year time horizon was chosen. The impact of alternative time horizons was tested in sensitivity analyses, which considered shorter (1-year, and within trial) and longer (10-year) time horizons. A 4-week cycle length was chosen for consistency with monitoring requirements in the product label. Costs and health benefits were discounted at an annual rate of 3.5 % and a halfcycle correction was implemented within the model. The model structure and assumptions were validated with Scottish experts.
2.Recent Advances in the Management of Difficult Constipation
Brian E. Lacy & John Levenick & Michael Crowell. Curr Gastroenterol Rep (2012) 14:306–312
Linaclotide is a 14-amino acid peptide that stimulates intestinal guanylate cyclase type-C (GC-C) receptors (see Fig. 1;). Linaclotide is acid stable and protease resistant with low bioavailability; it is undetectable in the systemic circulation at therapeutic doses. Activation of GC-C stimulates the production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP), which then increases the flow of electrolytes (HCO3- and Cl-) and water into the lumen of the GI tract (see Fig. 1). This is associated with faster GI transit. Stimulation of the GC-C receptor on intestinal epithelial cells and release of cGMP into the serosa leads to a reduction in visceral hyperalgesia.
3.New Options in Constipation Management
Mellar Davis & Pamela Gamier. Curr Oncol Rep (2015) 17: 55
Linaclotide is a first-in-class minimally adsorbed 14-aminoacid peptide agonist of guanylate cyclase C drug that acts on the intestinal enterocyte. The result is stimulation of chloride channels (CIC-2) and increase secretion of fluid into the gut lumen (Fig. 1). It is presently licensed for CIC and IBS-C in the USA. Oral bioavailability is 0.1 %, and less than 1 % is excreted in the stool in the first 24 h. Linaclotide undergoes proteolysis within the GI tract. However, it is resistant to pepsin, trypsin, aminopeptidases, and chymotrypsin proteolysis and thus is able to bind to duodenal and jejunal chloride channels. Linaclotide is converted to an active metabolite (MM-419447) which has the same pharmacodynamics and pharmacokinetics as the parent drug. Besides increasing luminal fluid, linaclotide also increases GI transit and reduces visceral hypersensitivity.
4.Linaclotide, Novel Therapy for the Treatment of Chronic Idiopathic Constipation and Constipation-Predominant Irritable Bowel Syndrome
Maria I. Vazquez-Roque · Ernest P. Bouras. Adv Ther (2013) 30(3):203–11.
A randomized, double-blind, placebocontrolled efficacy trial of linaclotide was conducted to evaluate its safety in 42 patients with CC. Patients were randomized to receive 100, 300, or 1,000 μg of linaclotide or placebo once daily for 14 days. Rebound constipation was assessed in an 8-day posttreatment period. Efficacy parameters were daily bowel movements using weekly rates of spontaneous bowel movements (SBM), complete SBM (CSBM), stool consistency, straining, and complete evacuation. At all doses studied, linaclotide produced an increase in SBM and CSBM compared to the placebo.