Characterisation of intravenous pharmacokinetics in Göttingen minipig and clearance prediction using established in vitro to in vivo extrapolation methodologies.

The use of the Göttingen 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 Göttingen minipig, using a comprehensive set of compounds.In vivo clearance was determined in Göttingen 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 Göttingen 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.

Current-induced forces and hot spots in biased nanojunctions.

We investigate theoretically the interplay of current-induced forces (CIFs), Joule heating, and heat transport inside a current-carrying nanoconductor. We find that the CIFs, due to the electron-phonon coherence, can control the spatial heat dissipation in the conductor. This yields a significant asymmetric concentration of excess heating (hot spot) even for a symmetric conductor. When coupled to the electrode phonons, CIFs drive different phonon heat flux into the two electrodes. First-principles calculations on realistic biased nanojunctions illustrate the importance of the effect.