Towards a translational physiologically-based pharmacokinetic (PBPK) model for receptor-mediated transcytosis of anti-transferrin receptor monoclonal antibodies in the central nervous system

In this manuscript, we present a translational physiologically-based pharmacokinetic (PBPK) model to characterize receptor-mediated transcytosis (RMT) of anti-transferrin receptor (TfR) monoclonal antibodies (mAbs) in the central nervous system (CNS). The model accounts for the state-of-the-art knowledge of the brain's anatomy and physiology, and physiological parameters were fixed according to different species. By estimating a few parameters associated with the TfR concentration, the TfR turnover, and the internalization rate, the model simultaneously characterizes plasma, whole brain, interstitial fluid (ISF), and cerebrospinal fluid (CSF) PK of unbound and bound anti-TfR mAbs with different binding affinities in mice, rats, and monkeys obtained from various literature sources within a threefold prediction error. The final PBPK model was validated using external anti-TfR mAb PK data in mice and monkeys with different affinities and doses. The simulation reasonably predicted plasma and brain PK of monovalent/bivalent anti-TfR mAbs within a threefold prediction error and characterized a bell-shaped relationship between the brain ISF/plasma AUC ratio and the K-D value. Although further refinements of the PBPK model and clinical validation are required, this PBPK model may provide physiologically-based translation of CNS disposition of anti-TfR mAbs by accounting for the physiological difference of the endogenous RMT system among different species. The PBPK model may also guide selection of other endogenous receptors, lead optimization, and clinical development of novel CNS-targeted mAbs.

Automated summary

In this manuscript, a translational PBPK model was presented to characterize the receptor-mediated transcytosis of anti-TfR mAbs in the CNS. The model takes into account the brain's anatomy and physiology and fixed physiological parameters based on different species. By estimating several parameters associated with TfR concentration, turnover, and internalization rate, the model characterizes the PK of unbound and bound anti-TfR mAbs in plasma, whole brain, interstitial fluid, and cerebrospinal fluid in mice, rats, and monkeys. The model was validated using external PK data in mice and monkeys with different affinities and doses. The simulation reasonably predicted the PK properties of anti-TfR mAbs in plasma and brain and revealed a relationship between brain ISF/plasma AUC ratio and K-D value.