PBPK model for antibody disposition in mouse brain: validation using large-pore microdialysis data

The objective of this manuscript was to validate a physiologically-based pharmacokinetic (PBPK) model developed to characterize brain pharmacokinetics (PK) of monoclonal antibodies (mAbs) using novel large-pore microdialysis data generated in mice. To support this objective, brain, CSF, and ISF PK of a human anti-tetanus toxin (TeTx) antibody was measured in mice following intraperitoneal (IP) administration. This antibody has no binding in mice. In addition, our recently published mouse brain PK data generated following intravenous (IV) and IP administration of trastuzumab in mice, and other published PK data for brain disposition of antibody in mice, were used to evaluate the PBPK model. All the model parameters were obtained from literature or kept the same as in our previously published manuscript. The revised PBPK model was able to characterize the PK of antibodies in mice brain, CSF, and ISF reasonably well (i.e., within a three-fold error). However, a priori selected parameters led to underprediction of ISF PK during the initial phase of the profile. A local sensitivity analysis suggested that minor changes in several brain-related parameters can help overcome this discrepancy, where an increase in the convective flow of antibodies across BBB was found to be the most parsimonious way to capture all the PK profiles well. However, the presence of this pathway needs further validation. As such, here we have presented an improved PBPK model to characterize and predict the PK of mAbs in different regions of the mouse brain following systemic administration. This model can serve as a quantitative tool to facilitate the discovery, preclinical evaluation, and preclinical-to-clinical translation of novel antibodies targeted against CNS disorders.

Automated summary

This manuscript presents an improved physiologically-based pharmacokinetic (PBPK) model to characterize and predict the brain pharmacokinetics (PK) of monoclonal antibodies (mAbs) in mice. The revised model was able to reasonably describe the PK of antibodies in the brain, cerebrospinal fluid (CSF), and interstitial fluid (ISF) with a three-fold error. However, it underestimated the ISF PK in the initial phase. A local sensitivity analysis suggested that minor changes in brain-related parameters, particularly an increase in convective flow across the blood-brain barrier (BBB), could resolve this discrepancy. The presence of this pathway requires further validation. This model can be a valuable quantitative tool for the discovery, preclinical evaluation, and translation of novel antibodies for central nervous system (CNS) disorders.