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

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Abstract

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.

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Acknowledgements

Florie Le Prieult, Colin Phipps, and Mario Mezler are employees of AbbVie and may own AbbVie stock. AbbVie sponsored and funded the animal study; contributed to the design; participated in the collection, analysis, and interpretation of data, and in writing, reviewing, and approval of the final publication. We would like to thank all AbbVie staff who helped for the execution and analysis of the studies mentioned in this manuscript: Ina Mairhofer, Aysel Güler, Gudrun Plotzky, Philipp Münzer, Lisa Riesbeck, Franziska Hanke, Klaus Diry, Khader Awwad, Klaus Magin, and Volker Berweck.

Funding

D.K.S. is supported by the grant from the Center for Protein Therapeutics (CPT) at the University at Buffalo, National Institute of General Medical Sciences Grant [GM114179], National Institute of Allergy and Infectious Diseases Grant [AI138195], and National Cancer Institute grants [R01CA246785 and R01CA256928].

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Authors and Affiliations

  1. Department 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

    Shengjia Wu & Dhaval K. Shah

  2. Drug Metabolism and Pharmacokinetics, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, Ludwigshafen, Germany

    Florie Le Prieult & Mario Mezler

  3. AbbVie Inc., 1 N Waukegan Road, North Chicago, IL, 60064, USA

    Colin J. Phipps

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  1. Shengjia Wu
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SW and FLP did the work and wrote the first draft, all authors edited/reviewed the manuscript.

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Correspondence to Dhaval K. Shah.

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Wu, S., Le Prieult, F., Phipps, C.J. et al. PBPK model for antibody disposition in mouse brain: validation using large-pore microdialysis data. J Pharmacokinet Pharmacodyn 49, 579–592 (2022). https://doi.org/10.1007/s10928-022-09823-x

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