Translational physiologically-based pharmacokinetic model for ocular disposition of monoclonal antibodies

AbstractWe have previously published a PBPK model comprising the ocular compartment to characterize the disposition of monoclonal antibodies (mAbs) in rabbits. While rabbits are commonly used preclinical species in ocular research, non-human primates (NHPs) have the most phylogenetic resemblance to humans including the presence of macula in the eyes as well as higher sequence homology. However, their use in ocular research is limited due to the strict ethical guidelines. Similarly, in humans the ocular samples cannot be collected except for the tapping of aqueous humor (AH). Therefore, we have translated this rabbit model to monkeys and human species using literature-reported datasets. Parameters describing the tissue volumes, physiological flows, and FcRn-binding were obtained from the literature, or estimated by fitting the model to the data. In the monkey model, the values for the rate of lysosomal degradation for antibodies (Kdeg), intraocular reflection coefficients ( σaq, σret,σcho), bidirectional rate of fluid circulation between the vitreous chamber and the aqueous chamber (QVA), and permeability-surface area product of lens (PSlens) were estimated; and were found to be 31.5  h−1, 0.7629, 0.6982, 0.9999, 1.64  × 10–5 L/h, and 4.62  × 10–7 L/h, respectively. The monkey model could capture the data in plasma, aqueous humor, vitreous humor and retina reasonably well with the predictions being within twofold of the observed values. For the human model,...
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research