(M-077) Ocular Pharmacokinetic/Pharmacodynamic Modeling of Drug Release from Single- and Bi-Layered Polymeric Microspheres for Retinal Conditions

Mohammad Aminul Islam – University at Buffalo, The State University of New York; Sarita Das – University at Buffalo, The State University of New York; Md Tanben Rahman – University at Buffalo, The State University of New York; Eduardo Chacin Ruiz – University at Buffalo, The State University of New York; Katelyn Swindle-Reilly – The Ohio State University; Ashlee Ford Versypt – University at Buffalo, The State University of New York

Objectives: Neovascular (wet) age-related macular degeneration (AMD) is a progressive eye disease characterized by the formation of abnormal, leaky blood vessels in the macula, the central region of the retina. These pathological blood vessels are driven by elevated levels of vascular endothelial growth factor (VEGF). Current treatment options for this and other retinal conditions require frequent intravitreal injections (IVT) of anti-VEGF drugs like abicipar pegol [1] and ranibizumab [2] to inhibit VEGF activity. However, frequent IVT injections are associated with pain, anxiety, and patient discomfort, highlighting the need for alternative drug delivery strategies. Drug delivery systems (DDSs) offer a promising solution by providing sustained drug release, potentially reducing the frequency of injections.

Methods: This study combines the release dynamics from single- and bi-layered microspheres as DDSs [3] with multi-compartment pharmacokinetic/pharmacodynamic (PK/PD) model of anti-VEGF agents (abicipar [1] and ranibizumab [2]) and VEGF inhibition. The model simulates drug distribution across key ocular compartments—including the vitreous, aqueous humor, retina, choroid, and serum—and evaluates VEGF pharmacodynamic suppression in the vitreous and aqueous humor. Drug release from the microspheres is simulated using Fick’s second law of diffusion, while species dynamics in the PK/PD model are described by mass action kinetics and simulated using ordinary differential equations.

Results: Simulations demonstrate that DDSs significantly prolong anti-VEGF drug release and enhance VEGF pharmacodynamic suppression, particularly with higher initial drug loading (1–2 mg for ranibizumab, 0.1–0.5 mg for abicipar). Both single-layered and bi-layered DDS architectures were evaluated, with results indicating that microsphere structure and size play critical roles in determining drug release kinetics and therapeutic effectiveness. We also examined the impact of different drug loading, microsphere sizes, and parameter variations on the VEGF pharmacodynamic suppression times. The microsphere radius nonlinearly impacted drug distribution by extending pharmacodynamic suppression times observed in both the vitreous and aqueous humor.

Conclusions: Our findings indicate that DDSs offer a promising approach to enhance the duration of VEGF pharmacodynamic suppression, particularly in the retina, compared to conventional IVT injections. Optimizing key parameters—such as initial drug loading, DDS structure (single-layer vs. bi-layered), microsphere radius, dissociation constant, and binding kinetics—further improved pharmacodynamic suppression times. The combined modeling approach offers a robust framework for optimizing DDSs design parameters and guiding future experimental and clinical developments in sustained ocular drug delivery.

Acknowledgments: This work was supported by National Institutes of Health grant R35GM133763 to ANFV, R01EB032870 to KESR and ANFV, and the University at Buffalo.

Citations: [1] Luu, K. T., et al., “A mechanistic and translational pharmacokinetic-pharmacodynamic model of abicipar pegol and vascular endothelial growth factor inhibition,” Journal of Pharmacology and Experimental Therapeutics 373.2 (2020): 184-192.
[2] Hutton-Smith, L. A., et al., “Theoretical insights into the retinal dynamics of vascular endothelial growth factor in patients treated with ranibizumab, based on an ocular pharmacokinetic/pharmacodynamic model,” Molecular Pharmaceutics 15.7 (2018): 2770-2784.
[3] Chacin Ruiz, E. A., et al., “Mathematical modeling of drug delivery from bi-layered core-shell polymeric microspheres,” bioRxiv (2024): 2024.01.11.575289.

Keywords: Polymeric Drug Delivery Systems, Pharmacokinetics/Pharmacodynamics Model, Ocular