Physiologically Based Biopharmaceutics Modelling of the Effect of a Permeability Enhancer on the Absorption of a Highly Soluble and Poorly Permeable Small Peptide in Humans
6 November 2024Compound A is a highly soluble, highly protein bound and poorly permeable small peptide. In preclinical species, distribution volume is low (cynomolgus monkey ~0.35 L, dog ~0.46 L). Transitioning to clinical settings where oral administration is preferred over parenteral routes, an enteric coated (EC) tablet was formulated for Compound A.
Given its poor permeability, sodium salcaprozate (SNAC), a permeability enhancer, was incorporated into the formulation. SNAC is proposed to facilitate the opening of tight junctions within the small intestine, thereby promoting paracellular absorption [1]. It has been reported that in vivo dissolution of EC formulations might be delayed compared to their in vitro counterparts, which may influence exposure [2].
It was hypothesised that using Physiologically Based Biopharmaceutics (PBB) Modelling, focusing on the alteration of intestinal paracellular permeability induced by SNAC, and variability in enteric coating performance could explain the pharmacokinetics variability of compound A.
The aim of the study was to develop a PBB model of Compound A based on variable permeability changes caused by varying local lumen SNAC concentrations; and by incorporating different dissolution lag times, to explain the variability of the SNAC effect leading to variability in Compound A exposure