Mechanistic <i>in vitro</i>-<i>in vivo</i> extrapolation (IVIVE) approach using a biomimetic <i>in vitro</i> system for the prediction of hepatic clearance.

Abstract

This study proposes a novel <i>in vitro</i>-<i>in vivo</i> extrapolation (IVIVE) strategy that integrates a patented biomimetic <i>in vitro</i> system with pharmacokinetic modeling to improve the prediction of <i>in vivo</i> 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 <i>in vivo</i> hepatic clearance values derived from the <i>in vitro</i> model were consistent with those reported <i>in vivo</i>, 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.