Ravi Kumar Jairam1, Maria Franz2, Dr. Anna-Kaisa Rimpelä3, Dr. Nina Hanke2, Dr. Prof. Lars Kuepfer1
1Institute for Systems Medicine with Focus on Organ Interaction, University Hospital RWTH Aachen, 2Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, 3Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG
Objectives: Intravitreal (IVT) injection of protein therapeutics is widely used in the treatment of various ocular diseases. Physiologically based ocular models (PBOMs) can significantly support a mechanistic understanding of physiological processes governing the disposition of biologics in the eye. In this study we have developed PBOMs for rabbits and monkeys, two important preclinical species in ocular pharmaceutical development, to simulate the ocular pharmacokinetics (PK) of protein therapeutics such as bevacizumab, TMAB001 and lampalizumab following IVT administration. Methods: We developed PBOMs that integrate physiological, anatomical, and biochemical parameters to simulate the ocular PK of therapeutic proteins [1, 2]. The models build upon a previously published compartmental eye model for rabbits, which includes vitreous, aqueous, and retina compartments [3]. We extended the existing PBOM by incorporating a serum compartment to describe the systemic drug exposure following IVT administration. The PBOMs were manually fitted to experimental concentration-time profile data from vitreous, aqueous humor, retina and serum of rabbits for bevacizumab, TMAB001, and lampalizumab. Model enhancements included strain-specific information and dose adjustments to improve bevacizumab predictions. The refined rabbit PBOMs were subsequently used for the development of PBOMs in monkeys using reported datasets of the same biologics. Retinal pigment epithelium permeabilities (pRPE), aqueous clearances, as well as vitreous and serum half-lives were estimated, while other parameters such as internal limiting membrane permeabilities (pILM) derived from the hydrodynamic radii, were fixed. Results: The final PBOMs demonstrated good model performance simulating the experimentally observed protein therapeutic concentrations across multiple ocular compartments in both rabbits and monkeys. In rabbits, the estimated vitreal half-lives were 5.08 days for bevacizumab, 5.36 days for TMAB001, and 3.23 days for lampalizumab. In monkeys, the corresponding values were 3.20, 2.80, and 1.91 days, respectively. The estimated vitreal half-life exhibited a consistent trend across both species, with shorter half-lives observed in monkeys compared to rabbits. Bevacizumab aqueous clearance differed between rabbit strains, being lower in Dutch Belted rabbits (2.12 µL/min) compared to New Zealand White rabbits (2.89 µL/min), while lampalizumab clearance in New Zealand White rabbits was 2.99 µL/min, comparable to previous findings [4, 5]. In monkeys, aqueous clearance values were consistent for TMAB001 and lampalizumab, confirming the reported value of 1.71 µL/min [5]. Bevacizumab in monkeys, however, exhibited a slightly higher aqueous clearance than the reported value [5]. For all protein therapeutics investigated, the estimated pRPE was lower than the pILM, consistent with the fact that the RPE forms a tighter barrier compared to the ILM [6, 7]. The observed serum half-lives were generally found to be similar to vitreous half-lives and longer than the half-lives calculated from the serum elimination rate constants. This indicates the presence of flip-flop kinetics where slow drug diffusion from the vitreous to the systemic circulation becomes the rate-limiting step in the elimination. For one of the rabbit studies and both monkey datasets of bevacizumab, however, the observed serum half-life was longer than the vitreous half-life. Conclusions: The developed models demonstrate good model performance describing the experimental data of different biologics, including IgGs and their fragments. Our findings highlight interspecies differences, and the importance of extended sampling periods and larger sample sizes in ocular PK studies to draw more definitive conclusions. PBOMs hold great promise to support the development of protein therapeutics and other biologics for ocular drug development, helping to refine intraocular delivery strategies, study design and sampling schemes. Furthermore, the advancement and use of PBOMs in the future might help reduce the reliance on non-human primates in drug development, thereby supporting the ethical principles of 3R-animal welfare.
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Reference: PAGE 33 (2025) Abstr 11478 [www.page-meeting.org/?abstract=11478]
Poster: Drug/Disease Modelling - Absorption & PBPK