Mechanism-Based Large Animal PK Strategies to Accelerate Oral Peptide Development

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).