Despite the positive preclinical data, the development of antibody-based therapeutic for CNS disorders has shown challenges in achieving significant therapeutic effects. Among clinical trials using antibodies for treating the Alzheimer’s disease, the importance of dosing and the related antibody exposure in the CNS has been highlighted. However, not only the delivery of antibody is limited at the blood-brain barrier (BBB), but also the measurement of antibody concentration at the site-of-action in the CNS may not be applicable. Besides, the plasma and cerebrospinal fluid (CSF) PK of monoclonal antibodies (mAbs) show challenges to be used as a surrogate to estimate the drug concentration at the brain parenchyma space. While the direct measurement of mAb exposure in the brain interstitial fluid (ISF) following systemic administration can be conducted using microdialysis in animals, there is a need for a quantitative tool that can predict the mAb PK at the site-of-action in the brain, and preclinical-to-clinical translation of mAbs being developed against CNS disorders. A physiologically-based pharmacokinetic (PBPK) model for the CNS accounts for known anatomy and physiology of the brain, including the presence of distinct the BBB and the blood-cerebrospinal fluid (CSF) barrier. It can be used to characterize brain disposition of mAbs in the mouse, rat, monkey and human by only changing the physiological parameters. Such model was first fitted to the rat dataset, and the model was validated using mouse, monkey and human's mAb PK data in the CNS. The proposed model can be further expanded to account for target engagement, disease pathophysiology, and novel mechanisms, to support discovery and development of novel CNS targeting mAbs.
Upon completion, the participant will be able to address the challenges in the development of antibody-based therapies for the CNS disorders
Upon completion, the participant will be able to understand some limitations of current modeling approaches for the mAb PK in the brain
Upon completion, the participant will be able to describe a PBPK model for antibody disposition in the brain
Upon completion, the participant will be able to understand a general process of the model fitting, validation, and application