Characterisation of Intravenous Pharmacokinetics in Göttingen Minipig and Clearance Prediction Using Established in Vitro to in Vivo Extrapolation Methodologies

The use of the Gottingen minipig as an animal model for drug safety testing and prediction of human pharmacokinetics (PK) continues to gain momentum in pharmaceutical research and development. The aim of this study was to evaluate in vitro to in vivo extrapolation (IVIVE) methodologies for prediction of hepatic, metabolic clearance (CLhep,met) in Gottingen minipig, using a comprehensive set of compounds. In vivo clearance was determined in Gottingen minipig by intravenous cassette dosing and hepatocyte intrinsic clearance, plasma protein binding and non-specific incubation binding were determined in vitro. Prediction of CLhep,met was performed by IVIVE using conventional and adapted formats of the well-stirred liver model. The best prediction of in vivo CLhep,met from scaled in vitro kinetic data was achieved using an empirical correction factor based on a 'regression offset' of the IVIV relationship. In summary, these results expand the in vitro and in vivo PK knowledge in Gottingen minipig. We show regression corrected IVIVE provides superior prediction of in vivo CLhep,met in minipig offering a practical, unified scaling approach to address systematic under-predictions. Finally, we propose a reference set for researchers to establish their own 'lab-specific' regression correction for IVIVE in minipig.