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Abstract

Monoclonal antibodies (mAbs) have limited brain penetration, posing a challenge for central nervous system (CNS) drug development. Physiologically based pharmacokinetic (PBPK) models can aid prediction, but existing frameworks often lack the ability to make mAb-specific predictions a priori. This study refined an existing rat brain PBPK model by adding physiologically relevant sub-compartments and developed an in-vitro to in-vivo extrapolation (IVIVE) framework using scaling factors to incorporate in-vitro apparent permeability (Papp) data for mAb brain penetration predictions. Implemented in MoBi®, the updated model enabled mAb-specific cerebrospinal fluid (CSF) predictions from Papp measurements. For non-receptor-mediated transport (non-RMT) mAbs, the IVIVE framework reduced absolute average CSF area-under-the-concentration-curve (AUC) percentage prediction error (%PE) by 295.2% (410.1 to 114.9) compared to a conventional fixed permeability model prediction based on trastuzumab. The approach was further evaluated using datasets that included FC5-modified mAbs, yielding an absolute average CSF AUC %PE of 64.5. Incorporating a TMEM30A-mediated RMT mechanism into the model structure provided a more mechanistic representation and further reduced the CSF AUC %PE of FC5-modified mAbs to 16.2. The IVIVE framework offers a broadly applicable, low-data approach, while the TMEM30A mechanistic model achieves highly accurate predictions when specific biological details are available. Together, these strategies provide flexible modeling options, balancing generalizability and mechanistic specificity. The rat brain PBPK model was also translated to mice using permeability values from the rat model without adjustment, achieving an absolute average %PE of 31.5% for CSF concentrations. These results suggest that mAb permeability is conserved across species, supporting cross-species PBPK applications. Further validation in non-human primates and humans will be essential to confirm translational utility and guide the development of mAbs targeting the CNS.