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Physiologically Based Pharmacokinetic Modeling to Characterize the Effect of Molecular Charge on Whole-Body Disposition of Monoclonal Antibodies

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Abstract

Motivated by a series of work demonstrating the effect of molecular charge on antibody pharmacokinetics (PK), physiological-based pharmacokinetic (PBPK) models are emerging that relate in silico calculated charge or in vitro measures of polyspecificity to antibody PK parameters. However, only plasma data has been used for model development in these studies, leading to unvalidated assumptions. Here, we present an extended platform PBPK model for antibodies that incorporate charge-dependent endothelial cell pinocytosis rate and nonspecific off-target binding in the interstitial space and on circulating blood cells, to simultaneously characterize whole-body disposition of three antibody charge variants. Predictive potential of various charge metrics was also explored, and the difference between positive charge patches and negative charge patches (i.e., PPC-PNC) was used as the charge parameter to establish quantitative relationships with nonspecific binding affinities and endothelial cell uptake rate. Whole-body disposition of these charge variants was captured well by the model, with less than 2-fold predictive error in area under the curve of most plasma and tissue PK data. The model also predicted that with greater positive charge, nonspecific binding was more substantial, and pinocytosis rate increased especially in brain, heart, kidney, liver, lung, and spleen, but remained unchanged in adipose, bone, muscle, and skin. The presented PBPK model contributes to our understanding of the mechanisms governing the disposition of charged antibodies and can be used as a platform to guide charge engineering based on desired plasma and tissue exposures.

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Data Availability

All relevant data have been included in this paper. Raw data can be provided upon reasonable request.

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Funding

This work was funded by the Center of Protein Therapeutics at the University at Buffalo. DKS is supported by 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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  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, 455 Pharmacy Building, Buffalo, Ney York, 14214-8033, USA

    Shufang Liu & Dhaval K. Shah

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S.L. and D.K.S. conceptualized the study. S.L. performed data collection and modeling analysis. S.L. wrote the first draft and D.K.S. revised the manuscript.

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Correspondence to Dhaval K. Shah.

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Liu, S., Shah, D.K. Physiologically Based Pharmacokinetic Modeling to Characterize the Effect of Molecular Charge on Whole-Body Disposition of Monoclonal Antibodies. AAPS J 25, 48 (2023). https://doi.org/10.1208/s12248-023-00812-7

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