Development of a physiologically-based pharmacokinetic model for ocular disposition of monoclonal antibodies in rabbits
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ORIGINAL PAPER
Development of a physiologically-based pharmacokinetic model for ocular disposition of monoclonal antibodies in rabbits David Bussing1 • Dhaval K. Shah1 Received: 30 March 2020 / Accepted: 14 August 2020 Ó Springer Science+Business Media, LLC, part of Springer Nature 2020
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 antibodybased 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. Keywords Eye Ocular pharmacokinetics Antibody Rabbit Physiologically-based pharmacokinetic model
Introduction Diseases of the eye have significant impacts on the lives of patients ranging from transient irritation to irreversible vision loss. Of the ocular disorders, age-related macular degeneration (AMD) and diabetic retinopathy (DR) are among the leading causes of blindness and are primary indications for protein therapeutics [1, 2]. In fact, all four FDA-approved therapies for AMD and DR are macromolecules: Macugen (pegaptanib, Gilead Sciences, Inc), Lucentis (ranibizumab, Genentech, Inc), Eylea (aflibercept, Regeneron Pharmaceuticals, Inc.), and Beovu (brolucizumab, Novartis International AG). With AMD alone expected to reach a global market of $10.4 billion by 2024,
& Dhaval K. Shah [email protected] 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
research in eye disease remains active and will benefit greatly from new tools that accelerate protein therapeutic drug development [3]. One such tool is pharmacokinetic (PK) models, which can help in characterization and a priori prediction of the ocular PK of protein therapeutics. Existing ocular PK models for protein therapeutics take
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