In vivo assessment of a delayed release formulation of larazotide acetate indicated for celiac disease using a porcine model
Open Access
- 12 April 2021
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 16 (4), e0249179
- https://doi.org/10.1371/journal.pone.0249179
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.Funding Information
- Innovate Biopharmaceuticals (91690)
- Innovate Biopharmaceuticals (91690)
This publication has 37 references indexed in Scilit:
- Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo‐controlled studyAlimentary Pharmacology & Therapeutics, 2012
- A Randomized, Double-Blind Study of Larazotide Acetate to Prevent the Activation of Celiac Disease During Gluten ChallengeThe American Journal of Gastroenterology, 2012
- Larazotide acetate promotes tight junction assembly in epithelial cellsPeptides, 2012
- Larazotide acetate regulates epithelial tight junctions in vitro and in vivoPeptides, 2012
- Pharmacotherapy and management strategies for coeliac diseaseExpert Opinion on Pharmacotherapy, 2011
- Assessment of gastrointestinal pH, fluid and lymphoid tissue in the guinea pig, rabbit and pig, and implications for their use in drug developmentEuropean Journal of Pharmaceutical Sciences, 2011
- Pharmacokinetics, protein binding, and tissue distribution of orally administered cefpodoxime proxetil and cephalexin in dogsAmerican Journal of Veterinary Research, 2010
- The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT‐1001 in coeliac disease subjects: a proof of concept studyAlimentary Pharmacology & Therapeutics, 2007
- Alterations in intestinal permeabilityGut, 2006
- Intestinal luminal pH in inflammatory bowel disease: possible determinants and implications for therapy with aminosalicylates and other drugsGut, 2001