Abstract
Purpose :
Wet age-related macular degeneration (AMD) is a disease which slowly destroys ones’ central vision. It is the leading cause of central blindness worldwide. Wet AMD is characterised by neovascularisation, triggered by an excess of vascular endothelial growth factor (VEGF). These newly formed capillaries allow fluids to seep into the retina, damaging the local photoreceptors. Currently, there is no definitive cure for wet AMD. As such, intravitreal injections of anti-angiogenic drugs to reduce the abundance of retinal VEGF are the clinical gold standard for disease management, slowing the progression of vision loss. However, injections into the eye are unpleasant, and the fluid flow within the eye leads to relatively rapid drug elimination, resulting in the need for regular intravitreal injections.
Methods :
To understand the pharmacodynamics of Ranibizumab, a standard-of-care VEGF targeting antibody, we developed a two-compartment mathematical model describing the pharmacokinetics/pharmacodynamics (PK/PD) of Ranibizumab following a single intravitreal injection. A schematic of the model setup can be seen in (Figure 1). Using hierarchical Bayesian inference, we applied this model to analyse published animal (cynomolgus monkey) and human aqueous Ranibizumab and VEGF data. This strategy allowed us to infer model parameter distributions which describe key ocular properties and the pharmacodynamics of Ranibizumab. Moreover, this approach allowed us to understand the variability in VEGF suppression observed between patients and between species.
Results :
Our study suggests that the elimination rates for Ranibizumab and VEGF have the most notable effect on ocular drug retention. From our data analysis, it was evident that collection of aqueous Ranibizumab samples is necessary to capture the pharmacodynamics of Ranibizumab. Finally, this study indicates that the cynomolgus monkey is an appropriate animal model to predict clinical ocular Ranibizumab pharmacodynamics.
Conclusions :
The model developed in this study extends our understanding of the ocular pharmacology and retention of Ranibizumab. In future work, we will use this modelling framework to analyse pre-clinical anti-VEGF drug candidates to treat wet AMD.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.