Linaclotide Significantly Improves Post-Operative Ileus and Opiate-Induced Constipation in Rats

Purpose: Linaclotide acetate (MD-1100) is currently in Phase 2 clinical trials for the treatment of irritable bowel syndrome with constipation (IBS-C), chronic constipation and other gastrointestinal (GI) disorders. Linaclotide, a 14 amino acid peptide, acts by stimulating guanylate cyclase-C located on the intestinal epithelial surface and has been found to be minimally absorbed and well tolerated at the doses of up to 3 mg/day tested in Phase 1. Additionally, linaclotide has been found to exhibit the expected dose-related intestinal pharmacodynamic activity in normal healthy subjects. In the current study, linaclotide was assessed for efficacy in rat models of post-operative ileus and opiate-induced constipation. Methods: Female, CD rats (130–180g) were used in these studies. Post-operative ileus was induced by manual manipulation of the intestines following laparotomy. Opiate-induced constipation was produced following intraperitoneal dosing with morphine at 2.5 mg/kg. Animals were dosed orally with linaclotide or vehicle before receiving a charcoal meal used to track transit within the small intestine. Group numbers for each of the studies ranged from 8 to 10 rats. Results: In an in vivo model of post-operative ileus, linaclotide at a dose of 10ug/kg significantly accelerated transit (p≤ 0.01) compared to animals receiving vehicle alone. In the opiate-induced constipation model, linaclotide at doses of 25 and 50ug/kg significantly enhanced transit compared to animals receiving morphine (p= 0.004 and 0.002 respectively), while also returning transit to a rate comparable with animals not receiving morphine at doses as low as 12.5ug/kg (p= 0.426). Conclusions: In two different models of decreased intestinal transit, linaclotide treatment was associated with accelerated transit compared to control animals that received vehicle alone. These data support potential utility of linaclotide for the treatment of both post-operative ileus and opiate-induced constipation.