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Title: Modelling the pharmacokinetics and pharmacodynamics of macromolecules for the treatment of wet AMD
Author: Hutton-Smith, Laurence
ISNI:       0000 0004 7430 6803
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Wet age related macular degeneration (wet AMD) is a highly debilitating retinal disease, the third leading cause of blindness in the world and one the most expensive ocular conditions to care for. Wet AMD is characterised by the proliferation of neovasculature through the retinal posterior and theorised to be, at least in part, induced and driven by excess vascular endothelial growth factor (VEGF). Many current treatments for wet AMD utilise anti-VEGF macromolecules that bind to VEGF. The retina, however, remains a largely inaccessible, and delicate, anatomical region. Due to difficulties in collecting clinical and experimental data, mathematical modelling is playing an increasingly prominent role in understanding the distribution (Pharmacokinetics, PK) and drug-to-target interactions (Pharmacodynamics, PD) for treatments of wet AMD. This thesis will focus on ordinary/partial differential equation (ODE/PDE) models for the PK/PD of anti-VEGF therapeutics, administered via intravitreal (IVT) injection into the mammalian eye. We start in Chapter 2 with a 2-compartment PK/PD ODE model of drug-VEGF interactions in the eye, analysing a clinical dataset to estimate key binding parameters between VEGF and the typical anti-VEGF molecule, ranibizumab. In Chapter 3, we extend the PK ODE framework of the 2-compartment model to include a mechanistic description of the retina, to estimate retinal permeability to macromolecules used for treating wet AMD. In Chapter 4, using the retinal PK model, we reintroduce VEGF to predict concentrations of free VEGF in the retina post-IVT injection. Chapters 5 and 6 model a hypothetical class of anti-VEGF molecules designed to bind not only VEGF but also existing vitreal superstructures, analysing how dose and binding kinetics impact ocular retention. Alongside these models we present analogous PDE models, addressing whether the assumption that concentrations are homogeneous across anatomical regions, as implicit in ODE models, is appropriate for macromolecular PK/PD in the mammalian eye.
Supervisor: Gaffney, Eamonn A. ; Byrne, Helen M. ; Maini, Philip K. Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: PK/PD ; wet amd ; IVT injection ; mathematical modelling