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

Shengjia Wu1, Florie Le Prieult2, Colin J Phipps3

  • 1Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, 455 Pharmacy Building, Buffalo, NY, 14214-8033, USA.

Journal of Pharmacokinetics and Pharmacodynamics
|September 10, 2022
PubMed
Summary

This study validates a physiologically-based pharmacokinetic (PBPK) model for predicting brain pharmacokinetics (PK) of monoclonal antibodies (mAbs) in mice. The improved PBPK model accurately characterizes mAb distribution in brain, CSF, and ISF, aiding CNS drug development.

Keywords:
Brain pharmacokineticsMicrodialysisMonoclonal antibodyMousePBPK model

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Area of Science:

  • Pharmacokinetics and Drug Metabolism
  • Neuroscience and Neurology
  • Biotechnology and Biologics

Background:

  • Physiologically-based pharmacokinetic (PBPK) models are crucial for understanding drug disposition in the central nervous system (CNS).
  • Characterizing brain pharmacokinetics (PK) of monoclonal antibodies (mAbs) is challenging due to the blood-brain barrier (BBB).
  • Accurate PBPK models are needed to predict mAb brain penetration and guide the development of therapies for CNS disorders.

Purpose of the Study:

  • To validate and refine a PBPK model for characterizing brain PK of mAbs in mice.
  • To assess the model's ability to predict mAb distribution in brain, cerebrospinal fluid (CSF), and interstitial fluid (ISF).
  • To improve predictions of mAb brain disposition using novel microdialysis data.

Main Methods:

  • Validation of a PBPK model using large-pore microdialysis data in mice.
  • Measurement of brain, CSF, and ISF PK of a human anti-tetanus toxin (TeTx) antibody after intraperitoneal (IP) administration.
  • Incorporation of published PK data for trastuzumab (IV and IP) and other antibodies in mice.
  • Local sensitivity analysis to identify key parameters influencing model predictions.

Main Results:

  • The revised PBPK model reasonably characterized antibody PK in mouse brain, CSF, and ISF within a three-fold error.
  • Initial underprediction of ISF PK was observed with a priori parameters.
  • Sensitivity analysis indicated that increased convective antibody flow across the BBB was the most effective adjustment for accurate PK profile prediction.

Conclusions:

  • An improved PBPK model effectively characterizes and predicts mAb PK in various mouse brain regions after systemic administration.
  • The model serves as a valuable tool for the discovery and preclinical evaluation of CNS-targeted antibody therapeutics.
  • Further validation of the convective BBB transport pathway is warranted.