The important role of hierarchical Bayesian inference in understanding macular degeneration treatment strategies #

Jessica Crawshaw, Eamonn Gaffney, Philip Maini, Antonello Caruso, Michael Gertz

15:50 Monday in 4Q56.

Part of the Mathematical and computational ophthalmology session.

Abstract #

Wet age-related macular degeneration (AMD) is a disease which slowly destroys ones’ central vision, with a huge impact on quality of life. It is the leading cause of central blindness worldwide. Wet AMD is characterised by neovascularisation, triggered by an unhealthy abundance of vascular endothelial growth factor (VEGF). These newly formed capillaries allow fluids to seep into the retina, damaging the local photoreceptors (critical light-sensing cells). Currently, there is no definitive cure for wet AMD. As such, intraocular injections of anti-angiogenic drugs to reduce the abundance of retinal VEGF is the clinical gold standard for disease management, slowing the progression of vision loss. However, injections into the eye are unpleasant, and the fluid dynamics within the eye leads to relatively rapid drug elimination, resulting in the need for regular intraocular injections.

In this talk, we will present and analyse a pharmacokinetic/pharmacodynamic (PK/PD) model of a standard-of-care antibody, ranibizumab, targeting VEGF. This model has been developed to improve our understanding of the ocular pharmacology of ranibizumab, and to provide a robust understanding of ranibizumab retention in the eye. Results from this PK/PD model are compared with published animal (cynomolgus monkey) and human data. We present a hierarchical Bayesian inference strategy to determine relevant parameter distributions. Using this strategy, we provide insight into the clinically observed inter-patient variability in VEGF suppression and drug retention. Finally, this model establishes the initial basis for a computational framework we are developing to mathematically compare the ocular PK/PD of ranibizumab with novel therapeutic strategies and other clinical anti-VEGF drugs in the treatment of AMD.