A predictive model for paracellular solute transport across vascular endothelia: Quantitative insight into factors affecting subcutaneous absorption.

This study presents a predictive computational model that simulates drug absorption across vascular endothelia after subcutaneous (SC) injection of small hydrophilic drugs (<20 kDa). A three-dimensional finite element model was constructed using COMSOL Multiphysics 6.3, treating SC tissue as a poroelastic medium. The model integrates interstitial fluid flow, SC tissue deformation, and both diffusive and convective drug transport via paracellular capillary uptake. Human plasma concentration-time data for various hydrophilic drugs, obtained from published literature, were used to estimate observed absorption rate constants. These were compared with predicted absorption rate constants from simulations and used to evaluate the model's accuracy. The model demonstrates that absorption rate decreases with increasing solute size and formulation viscosity. The absorption rate increases as tissue capillary density and capillary hydraulic conductivity increases at the site of injection. Incorporating solute aggregation into the numerical simulations improves the accuracy of the predicted absorption rate constant. Integrating a tissue-level vascular transport in silico model with human pharmacokinetics allows formulators to systematically evaluate variables that enhance the optimization of subcutaneous absorption.