Linaclotide has been approved for adults (≥18 years) with chronic constipation and constipation-predominat irritable bowel syndrome (IBS-C) (Gastroenterol & Hepatol 2012; 8: 653-60).
Linaclotide is a 14-amino acid peptide that stimulates guanylyl cyclase C (GCC) receptors. It mimics the endogenous peptides guanylin (15 amino acids) and uroguanylin (16 amino acids) which activate GCC through a cascade which activates CFTR to increase luminal levels of bicarbonate, chloride and water. This in turn improves gastrointestinal transit.
There were several trials undertaken to assess the efficacy of linaclotide in IBS-C:
- 47 patients (36 women) with IBS-C were treated with linaclotide (100 μg or 1000 μg) or placebo –5 day study. The 1000 μg dose significantly decreased colonic transit time compared with placebo. No serious adverse events were reported.
- 420 patients were enrolled in a 12-week, randomized, double-blind, placebo-controlled, dose-ranging study. The population was 92% female, 80% caucasian with a mean age of 44 years. 337 patients completed the study. There were improvements in the number of complete spontaneous bowel movements (CSBMs) per week and in abdominal pain. Additional results:
- With 300 μg dose, there were 3.93 CSBMs/week, with150 μg dose 2.79 CSBMs/week compared with 1.47 for placebo.
- With 300 μg dose, there was -0.90 in pain score, with 150 μg dose -0.71 compared with -0.49 for placebo. Overall, abdominal pain improved in 31.1-38.7% of linaclotide-treated patients compared with 22.7% of placebo-treated patients.
For chronic constipation, four trials (n=42, n=310, n=630, and n=642) have shown increased CSBMs/week. On average, a dose of 290-300 μg dose resulted in 1.8-2.7 CSBMs/week, a dose of 145-150 μg dose resulted in 1.6-2.0 CSBMs/week compared with 0.5-0.6 CSBMs/week for placebo. Changes in stool frequency were also reflected in quality of life scores. When linaclotide was stopped, patients reverted to similar stooling rates as placebo-treated patients but no rebound effects were noted.
Prior to approval of linaclotide, lubiprostone (Amitiza) had been the only FDA-approved medication for IBS-C. For chronic constipation, polyethylene glycol is another approved treatment.
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