At the 2024 ISSX-JSSX Joint Meeting, researchers from Quotient Sciences and Bristol Myers Squibb presented a poster exploring how modeling can be used to predict the impact of permeability enhancers on drug absorption.
Titled “Physiologically Based Biopharmaceutics Modeling of the Effect of a Permeability Enhancer on the Absorption of a Highly Soluble and Poorly Permeable Small Peptide in Humans”, the poster reviewed work performed on a highly soluble, poorly permeable small peptide with low distribution volume and high protein binding. To better enable oral delivery of the compound, researchers formulated an enteric-coated (EC) tablet with sodium salcaprozate (SNAC), a permeability enhancer.
Read highlights from the poster below, authored by Ricardo Diaz de Leon-Ortega, Ajay Saxena, Jonathan Brown, Dannielle Ravenhill, Kevser Sevim, and Zoe Kane. Download the poster to see additional findings.
Program objectives and design
In this study, the objective was to build a physiologically based biopharmaceutics (PBB) model that could simulate the effect of SNAC on Compound A absorption, while also accounting for variability in dissolution lag times.
To enable oral delivery of Compound A, researchers formulated an enteric-coated (EC) tablet with SNAC. Using PKSim/MoBi software, the team developed a model that linked SNAC concentration in the duodenum to changes in Compound A’s paracellular permeability. This allowed them to simulate how variability in dissolution timing affects drug absorption and exposure.
Key findings from the program
The model accurately predicted plasma concentration-time profiles for two EC tablet formulations (20 mg and 40 mg Compound A + 600 mg SNAC) in healthy volunteers. Predicted oral bioavailability (%F) ranged from 0.001% to 0.8%, aligning with preclinical observations in dogs and cynomolgus monkeys.
A linear relationship between SNAC concentration and paracellular permeability was used to simulate absorption, with longer dissolution lag times resulting in reduced permeability and lower drug exposure.
The model also successfully simulated IV administration of Compound A to estimate systemic exposure and validate oral predictions.
This modeling approach provides a valuable framework for predicting the pharmacokinetics of poorly permeable compounds that rely on permeability enhancers. It supports formulation optimization and helps explain inter-subject variability in clinical studies—ultimately accelerating the development of challenging oral drug candidates.
Download the poster to see additional findings and learn more about modeling & simulation services provided by Quotient Sciences.