Abstract
There is no FDA approved therapy for the treatment of celiac disease (CeD), aside from avoidance of dietary gluten. Larazotide acetate (LA) is a first in class oral peptide developed as a tight junction regulator, which is a lead candidate for management of CeD. A delayed release formulation was tested in vitro and predicted release in the mid duodenum and jejunum, the target site of CeD. The aim of this study was to follow the concentration versus time profile of orally administered LA in the small intestine using a porcine model. A sensitive liquid chromatography/tandem mass spectrometry method was developed to quantify LA concentrations in porcine intestinal fluid samples. Oral dosing of LA (1 mg total) in overnight fasted pigs resulted in time dependent appearance of LA in the distal duodenum and proximal jejunum. Peak LA concentrations (0.32-1.76 μM) occurred at 1 hour in the duodenum and in proximal jejunum following oral dosing, with the continued presence of LA (0.02-0.47 μM) in the distal duodenum and in proximal jejunum (0.00-0.43 μM) from 2 to 4 hours following oral dosing. The data shows that LA is available in detectable concentrations at the site of CeD.
Highlights
Celiac disease (CeD) is one of the most common autoimmune disorders affecting around 1% of the population worldwide [1, 2]
Gliadin indirectly stimulates the secretion of zonulin from the lamina propria of the intestine into the intestinal lumen, which leads to the binding of zonulin to purported apical receptors of the enterocyte
This study was designed to assess the in vivo delivery and gastrointestinal transit profile of the delayed release formulation of Larazotide acetate (LA) intended for use in CeD patients using a porcine model
Summary
Celiac disease (CeD) is one of the most common autoimmune disorders affecting around 1% of the population worldwide [1, 2]. CeD is defined as a chronic small intestinal immune mediated enteropathy that is precipitated by exposure to dietary gluten, which is broken down into immunologically active gliadin fragments in genetically predisposed individuals. Gliadin indirectly stimulates the secretion of zonulin from the lamina propria of the intestine into the intestinal lumen, which leads to the binding of zonulin to purported apical receptors of the enterocyte. This initiates a complex series of tight junction events that involves phosphorylation of tight junction proteins, which induces a loss of epithelial barrier function, exacerbating innate and adaptive immune responses [1, 3, 4].
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