Mechanistic - extrapolation (IVIVE) approach using a biomimetic system for the prediction of hepatic clearance.

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