Mechanistic in vitro–in vivo extrapolation (IVIVE) approach using a biomimetic in vitro system for the prediction of hepatic clearance

Abstract

This study proposes a novel in vitro–in vivo extrapolation (IVIVE) strategy that integrates a patented biomimetic in vitro system with pharmacokinetic modeling to improve the prediction of in vivo drug kinetics. The system employed a single-well plate design with various sizes of mesh inserts to simultaneously assess drug diffusion and cellular metabolism. Drug diffusion patterns were quantified and modeled using a Weibull distribution to establish mathematical relationships between pore size and kinetic parameters. The model was extended to predict the metabolic phase with two drugs, the metabolic conversion of diclofenac into 4-hydroxydiclofenac and metabolic clearance of testosterone in HepaRG cells. The predicted in vivo hepatic clearance values derived from the in vitro model were consistent with those reported in vivo, validating the approach. This integrated strategy enhances IVIVE accuracy and supports the 3 R (replacement, reduction, and refinement) principle by reducing the reliance on animal testing. The findings demonstrate the potential of combining biomimetic systems and mathematical modeling as a reliable platform for pharmacokinetic prediction in drug development.