Vanessa Baier1, Pavel Balazki, Marco Albrecht1, Alexander Kulesza1, Mariana Guimaraes Sa Correia1, Nina Nauwelaerts1, Laurence Dodd1, Venetia Karamitsou1, Marco Siccardi1, Stephan Schaller1
1ESQlabs GmbH
Objectives Treatment of ocular disorders (e.g., eye infection or macular degeneration) often requires optimization of delivery of drugs to the ocular tissues by either intravitreous infusion or topical administration. Physiologically based pharmacokinetics could combine a predictive framework for local biodistribution with cross species extrapolation, drug-drug-interaction, or extrapolation to special populations simulation [1], but most models lack detailed description of the eye physiology. We demonstrated feasibiity to develop re-usable ocular physiology modules for the PBPK platform of the Open Systems Pharmacology Suite (OSPS, PK-Sim and MoBi). [2] OSPS v12 has introduced modularisation, offering a structured framework to facilitate model integration and extension. This modularised approach is showcased based on published physiological PBPK structure [3,4] on the example of vancomycin, an antibiotic glycopeptide, as an ocular administration for the treatment of eye infection in two species. Methods A detailed eye physiology module containing the parametrised compartments of the eye (including tear fluid, aqueous humor, cornea, conjunctiva, vitreous, retina, choroid, sclera, iris/ciliary body) was developed for the species rabbit and human [3, 4]. The model is based on physiological knowledge and describes passive diffusion and tissue-composition-based partitioning of chemical compounds. The eye structure was implemented in a separate MoBi module and is compound-agnostic, allowing for broad applicability and re-usability across different compound models. Using the novel modularisation approach of the OSPS, a complex whole-body PBPK model based on three modules was implemented: 1) a compound-specific whole-body PBPK model of vancomycin [5], 2) the newly developed eye physiology module, and 3) an Emax module for describing the antibacterial efficacy of a compound. The final integrative PBPK model was used to simulate ocular exposure and the effect of vancomycin in the vitreous. Results The final model was able to reproduce systemic and eye tissue concentrations (data available for vitreous and aqueous humor) of vancomycin in rabbits and humans after intravenous and intravitreal administration (within 3-fold deviation) [6-10]. The effect of vancomycin on bacteria count in the vitreous of rabbits infected with endophthalmitis was simulated. [11] The model confirmed that ocular concentrations after IV administrations were insufficient to sterilise the vitreous staying below the minimal inhibitory concentration (MIC). [6, 7] Conclusion A complex ocular extension module was developed for use in OSPS v12 that is able to reproduce ocular exposure to drugs. This module was used to demonstrate a straightforward integration of a physiological extension into a drug-specific PBPK model and was further extended by an effect model. The combined ocular and whole-body PBPK/PD model was used to simulate ocular exposure of vancomycin in two species and predicted therapeutic efficacy for eye infection after different administration protocols. The model workflow can easily be applied to other compounds and be extended to more complex PD or QSP models.
[1] 1. Kuepfer, L., Fuellen, G. & Stahnke, T. Quantitative systems pharmacology of the eye: Tools and data for ocular QSP. CPT: Pharmacometrics & Systems Pharmacology 12, 288–299 (2023). [2] Open Systems Pharmacology Suite (OSPS) v12, https://github.com/Open-Systems-Pharmacology/Suite [3] Le Merdy, M. et al. Ocular Physiologically Based Pharmacokinetic Modeling for Ointment Formulations. Pharm Res 37, 245 (2020). [4] Rimpelä, A.-K. Ocular Pharmacokinetic Effects of Drug Binding to Melanin Pigment and the Vitreous Humor. (2018). [5] Vancomycin-Model. Open Systems Pharmacology (2021). [6] Ferencz, J. R. Vancomycin Concentration in the Vitreous After Intravenous and Intravitreal Administration for Postoperative Endophthalmitis. Arch Ophthalmol 117, 1023 (1999). [7] Homer, P., Peyman, G. A., Koziol, J. & Sanders, D. INTRAVITREAL INJECTION OF VANCOMYCIN IN EXPERIMENTAL STAPHYLOCOCCAL ENDOPHTHALMITIS. Acta Ophthalmologica 53, 311–320 (1975). [8] Meredith, T. A. et al. Vancomycin Levels in the Vitreous Cavity After Intravenous Administration. American Journal of Ophthalmology 119, 774–778 (1995). [9] Park, S. S. Intravitreal Dexamethasone Effect on Intravitreal Vancomycin Elimination in Endophthalmitis. Arch Ophthalmol 117, 1058 (1999). [10] Pryor, J. G., Apt, L. & Leopold, I. H. Intraocular Penetration of Vancomycin. Archives of Ophthalmology 67, 608–611 (1962). [11] Lefèvre, S. et al. Daptomycin versus Vancomycin in a Methicillin-Resistant Staphylococcus aureus Endophthalmitis Rabbit Model: Bactericidal Effect, Safety, and Ocular Pharmacokinetics. Antimicrob Agents Chemother 56, 2485–2492 (2012).
Reference: PAGE 33 (2025) Abstr 11331 [www.page-meeting.org/?abstract=11331]
Poster: Drug/Disease Modelling - Absorption & PBPK