Multi-Compartment Pharmacokinetic-Pharmacodynamic Modeling of Drug Delivery from Bi-Layered Polymeric Microspheres for Wet AMD

Wet (neovascular) age-related macular degeneration (nAMD) is an aggressive eye condition caused by the formation of abnormal leaky blood vessels located in the central area (macula) of the retina. These leaky blood vessels are associated with increased vascular endothelial growth factor (VEGF) levels. Current treatment options for nAMD involve repeated intravitreal injections into the eye with drugs including abicipar, ranibizumab, and bevacizumab, which all play a part in suppressing VEGF levels in the eye [1-3]. However, repeated injection is not an ideal treatment plan and can cause pain, anxiety, and disturbance for patients. Drug delivery systems (DDS) offer a solution to provide extended delivery of drugs.

Here, we connected pharmacokinetic/pharmacodynamic models of intravitreal injection of abicipar [1], ranibizumab [2], and bevacizumab [3] to the mathematical modeling of drug release from bi-layered polymeric microsphere DDS [4] to investigate drug release dynamics and VEGF suppression in the eye. The DDS consists of a drug-loaded core made of chitosan and an outer polycaprolactone layer. The inner layer controls the extended drug release after an initial burst release, whereas the outer layer protects the core from degradation. Our aim is to quantify the drug release dynamics and VEGF suppression from the DDS compared to existing regular injection models and optimize the DDS parameters, i.e., drug loading amount and radii of the inner and outer layer of the microsphere.

Our first model for abicipar mapped the resulting drug concentration and half-maximal inhibitory concentration (IC50) in eye compartments. This model helped us conclude that the DDS was more effective in holding the drug concentration above the IC50 value for an extended period compared to regular injection cycles. Our models for ranibizumab and bevacizumab also determined that the DDS could provide increased VEGF suppression over time. Additionally, we simulated the effect of variation in the initial drug loading amount and variations of the inner and outer radius of the DDS. All models found that decreasing the drug loading amount and the thickness of the sphere’s inner layer decreases the duration of drug release and VEGF suppression.

Our simulated results demonstrate the potential of DDS in nAMD treatment to decrease injection frequency, thereby reducing patient discomfort while still allowing extended drug release for longer VEGF suppression. Future goals of this research are to optimize the DDS model for the different drugs and to use the results in mathematical models for patient outcomes, including their visual acuity and retinal thickness.