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Development of a physiologically-based pharmacokinetic model for ocular disposition of monoclonal antibodies in rabbits

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Abstract

Development of protein therapeutics for ocular disorders, particularly age-related macular degeneration (AMD), is a highly competitive and expanding therapeutic area. However, the application of a predictive and translatable ocular PK model to better understand ocular disposition of protein therapeutics, such as a physiologically-based pharmacokinetic (PBPK) model, is missing from the literature. Here, we present an expansion of an antibody platform PBPK model towards rabbit and incorporate a novel anatomical and physiologically relevant ocular component. Parameters describing all tissues, flows, and binding events were obtained from existing literature and fixed a priori. First, translation of the platform PBPK model to rabbit was confirmed by evaluating the model’s ability to predict plasma PK of a systemically administered exogenous antibody. Then, the PBPK model with the new ocular component was validated by estimation of serum and ocular (i.e. aqueous humor, retina, and vitreous humor) PK of two intravitreally administered monoclonal antibodies. We show that the proposed PBPK model is capable of accurately (i.e. within twofold) predicting ocular exposure of antibody-based drugs. The proposed PBPK model can be used for preclinical-to-clinical translation of antibodies developed for ocular disorders, and assessment of ocular toxicity for systemically administered antibody-based therapeutics.

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Acknowledgements

D.K.S is supported by NIH grants GM114179, AI138195, and R01CA246785.

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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, NY, 14214-8033, USA

    David Bussing & Dhaval K. Shah

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Bussing, D., K. Shah, D. Development of a physiologically-based pharmacokinetic model for ocular disposition of monoclonal antibodies in rabbits. J Pharmacokinet Pharmacodyn 47, 597–612 (2020). https://doi.org/10.1007/s10928-020-09713-0

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