Modelling and Simulation of the Effect of a Permeability Enhancer on the Absorption of a Poorly Permeable Compound

Compound A is highly soluble at physiological pH, highly bound to proteins (%PPB >99.9%) and has poor permeability (Caco-2 Papp < 1 nm/s). In dog, the volume of distribution is low (50 mL/kg), clearance is 0.835 mL/h/kg and a mono-exponential decline in plasma concentration is observed. An enteric coated solid oral dosage form of compound A was developed. 

Due to its negligible intestinal permeability, the permeability enhancer Salcaprozate sodium (SNAC) was incorporated into the formulation. One mechanism proposed to explain the action of permeability enhancers is the transient opening of intestinal tight junctions (during a time window of ~20 minutes), leading to a temporary increase of paracellular permeability [1].

The objective of this work was to develop a reduced PBPK model for the oral administration of compound A in dogs, focusing on the alteration of paracellular permeability caused by SNAC.