{"id":542,"date":"2016-10-08T02:17:51","date_gmt":"2016-10-08T07:17:51","guid":{"rendered":"http:\/\/www.bocsci.com\/blog\/?p=542"},"modified":"2016-10-08T03:08:38","modified_gmt":"2016-10-08T08:08:38","slug":"linaclotide-management-of-difficult-constipation","status":"publish","type":"post","link":"https:\/\/www.bocsci.com\/blog\/linaclotide-management-of-difficult-constipation\/","title":{"rendered":"Linaclotide Management of Difficult Constipation"},"content":{"rendered":"

Linaclotide<\/a> is a 14-amino acid peptide that stimulates intestinal guanylate cyclase type-C (GC-C) receptors. Linaclotide is acid stable and protease resistant with low\u00a0bioavailability; it is undetectable in the systemic circulation at\u00a0therapeutic doses. Activation of GC-C stimulates the production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP), which then increases the flow of\u00a0electrolytes(HCO3-<\/sup>\u00a0and Cl–<\/sup>)\u00a0and water into the lumen of the\u00a0GI tract. This is associated with faster GI transit.\u00a0Stimulation of the GC-C receptor on intestinal epithelial cells\u00a0and release of cGMP into the serosa leads to a reduction in\u00a0visceral hyperalgesia.<\/p>\n

Johnston and colleagues were the first to investigate the\u00a0safety, tolerability, and efficacy of linaclotide in patients with\u00a0CC who met modified Rome II criteria. This multicenter,\u00a0placebo-controlled pilot study published in 2009, showed that\u00a0there was a trend towards a dose-dependent increase in the\u00a0frequency of weekly spontaneous bowel movements (SBMs)\u00a0and complete spontaneous bowel movements (CSBMs). Stool\u00a0consistency, straining, and patient reported outcomes also\u00a0improved in all dosing groups.<\/p>\n

\"851199-59-2\"<\/a><\/p>\n

Linaclotide – CAS 851199-59-2<\/a><\/h3>\n

These promising results led to a larger multicenter,\u00a0placebo-controlled study involving 310 CC patients defined\u00a0by modified Rome II criteria. Patients were randomized\u00a0to one of four linaclotide dosages (75, 150, 300, or 600 \u03bcg) or\u00a0placebo once daily for 4 weeks. The primary end point was the\u00a0change in mean weekly SBM frequency from the 14-day pretreatment period to the 4-week treatment period. Patients were\u00a0also analyzed using a responder definition of a weekly SBM\u00a0>\u00a03 and an increase of\u00a0>1 relative to baseline, for 3 of the 4\u00a0treatment weeks. Secondary endpoints included changes in\u00a0stool consistency, straining, abdominal discomfort, and bloating. Lembo and colleagues noted that the frequency of weekly SBMs increased significantly in a linear\u00a0response to increasing dosages of linaclotide (2.6, 3.3, 3.6,\u00a0and 4.3 for linaclotide doses of 75, 150, 300, and 600 \u03bcg,\u00a0respectively), compared to 1.5 for placebo (p<0.05 for each\u00a0linaclotide dosage group compared to placebo). The median\u00a0time to first SBM, mean number of CSBMs, stool consistency,\u00a0and severity of straining also demonstrated a significantly\u00a0improved dose-dependent relationship compared to placebo.\u00a0No rebound effect occurred during a 14-day post-treatment\u00a0surveillance period. Adverse events were reported in 33.8 %\u00a0of patients receiving the study drug and 31.9 % of placebo\u00a0(n.s.). The most commonly reported AEs were GI related, of\u00a0which diarrhea was the most frequent, 5.1 %\u201314.3 %, versus\u00a02.9 % of placebo patients. Only two cases of diarrhea were\u00a0graded as severe, both were in the 600 \u03bcg group and both\u00a0resulted in cessation of treatment.<\/p>\n

The most recent report on linaclotide describes data from\u00a0two parallel, randomized, placebo-controlled, doubleblinded trials using either 145 \u03bcg or 290 \u03bcg linaclotide or\u00a0placebo over 12-weeks in 1272 patients with CC.\u00a0Trial 01 consisted of 630 patients while trial 303 consisted\u00a0of 642 patients (median age 48; 89 % female). The primary\u00a0endpoint of both trials was defined a priori as both three or\u00a0more CSBMs\/week and an increase of at least one CSBM\/week from baseline for at least 9 out of the 12 weeks.\u00a0Secondary endpoints included measurements of stool frequency, stool consistency, severity of straining, abdominal\u00a0discomfort, bloating, and overall constipation severity. The\u00a0authors reported that once daily linaclotide produced early\u00a0and sustained improvement in bowel and abdominal symptoms, SBMs, and CSBMs within the first week of treatment.\u00a0For the 12-week study period the primary end point (12-week\u00a0CSBM overall responder for\u22659 of 12 weeks) was met in both\u00a0trial 01 (16.0 %, 21.3 % vs. 6.0 % for placebo, p=00.0012 and\u00a0p<0.0001) and 303 (21.2 % and 19.4 % vs. 3.3 %, p<0.0001).\u00a0These benefits remained when the data were pooled and\u00a0analyzed for weeks 1 through week 12. Secondary endpoints\u00a0including CSBMs\/week, SBMs\/week, stool consistency,\u00a0straining, constipation severity, abdominal discomfort, and\u00a0bloating were superior to placebo and statistically significant\u00a0in both studies for each dose of linaclotide. Trial\u00a0303 included a randomized 4-week withdrawal study that\u00a0included 538 of the 642 patients. A rebound effect was not\u00a0found during the withdrawal period, and patients initially\u00a0treated with placebo and then randomized to linaclotide noted\u00a0results similar to those initially treated with linaclotide. Quality of life assessments, using the PAC-QOL instrument,\u00a0showed an improvement in patients treated with linaclotide\u00a0compared to those treated with placebo (p<0.01). The authors\u00a0reported one death in this study\u2014it occurred due to an overdose\u00a0of fentanyl and was not thought related to the study drug.\u00a0Discontinuation rates due to AEs were 4.2 % in placebo-treated\u00a0patients, compared to 7.9 % in patients treated with 145 ug\u00a0linaclotide and 7.3 % in those treated with 290 ug of linaclotide.\u00a0Discontinuation of the study medication and AEs were primarily\u00a0GI\u2014related (e.g., diarrhea, flatulence, and abdominal pain). No\u00a0clinically significant differences were found among the 3 groups
\nwith regard to EKG results, vital signs, blood chemistries, urinalysis, or hematologic findings. Although the strict definition\u00a0for entrance into these studies was chronic constipation, using\u00a0modified\u00a0Rome\u00a0II\u00a0criteria,\u00a0it\u00a0is\u00a0reasonable\u00a0to\u00a0assume\u00a0that\u00a0many\u00a0of\u00a0these patients had difficult constipation, and thus these findings\u00a0are relevant for that population.<\/p>\n

 <\/p>\n

Reference:<\/p>\n

Brian E. Lacy & John Levenick & Michael Crowell. Curr Gastroenterol Rep (2012) 14:306\u2013312<\/p>\n","protected":false},"excerpt":{"rendered":"

Linaclotide is a 14-amino acid peptide that stimulates intestinal guanylate cyclase type-C (GC-C) receptors. Linaclotide is acid stable and protease resistant with low\u00a0bioavailability; it is undetectable in the systemic circulation […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[181],"tags":[328,327],"_links":{"self":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/542"}],"collection":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/comments?post=542"}],"version-history":[{"count":2,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/542\/revisions"}],"predecessor-version":[{"id":545,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/542\/revisions\/545"}],"wp:attachment":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media?parent=542"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/categories?post=542"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/tags?post=542"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}