AAPS eChalk Talk: Application Strategies of Large Animal Models in Oral Peptide Pharmacokinetics

Webinar Overview:

The development of oral peptide drugs faces multiple physiological barriers, including gastric acid degradation, enzymatic hydrolysis, the mucus layer barrier, and low permeability across the intestinal epithelium, resulting in extremely low bioavailability. Traditional pharmacokinetic (PK) evaluation methods, which rely primarily on peripheral blood AUC (area under the plasma concentration-time curve), are unable to differentiate the relative contributions of these individual barriers, thereby limiting the rational design of formulation optimization. To address this bottleneck, this study established four mechanism-based PK evaluation techniques with barrier-resolution capability using large animal models (dogs and non-human primates): (1) the pyloric ligation surgical model to independently assess gastric absorption contribution; (2) the portal vein/splenic vein dual-catheterization model to distinguish and quantify the absorption contributions of the stomach versus the intestine; (3) the intestinal segmental catheterization model to localize the absorption efficiency of specific intestinal segments (duodenum, jejunum, ileum, and colon); and (4) X-ray/CT imaging tracking technology to non-invasively monitor the disintegration, dispersion, and transit of formulations within the gastrointestinal tract. These models enable a full-chain analysis of the absorption bottlenecks of oral peptides, providing quantitative in vivo evidence for formulation strategies such as permeation enhancer screening, enteric coating localization, and release site matching, thereby driving the development of oral peptide formulations from ‘empirical trial-and-error’ toward ‘data-driven rational design’.