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lead supervisor:  Prof Eamonn Gaffney, Mathematical institute

Co-supervisor: Prof Philip Maini

Commercial partner: Roche, Switzerland

 

Ophthalmology drug development is a rapidly growing area aiming to fulfil the unmet medical need for durable and more efficacious treatments. In particular, the current standard of care for many treatments of retinal pathologies, such as wet age-related macular degeneration, requires intravitreal injections, which can exhibit poor drug retention within the eye. This not only leads to numerous unpleasant ocular injections but also has the prospect of limiting the target engagement at the therapeutic site of action. Although uncertainty in the levels of target engagement is not uncommon, it is also generally found to be predominantly associated with high attrition. This motivates the continuing development of a rational and quantitative mechanism-based computational modelling framework for understanding prospective ocular drug retention technologies, in particular their impact on drug levels at the site of action.

A major challenge here is that standard pharmacokinetic modelling is not applicable within the eye, thus requiring more complex simulation, with previous work focussed on compartmental models. However, compartmentalisation does not reflect the actual geometry of the eye, and relies on a well-mixed assumption that drug concentrations are uniform within each compartment, which are typically the vitreous, the anterior chamber and the retina. The heterogeneity associated with macular degeneration, where the macula is a specific part of the retina that is degenerating, highlights the potential value of moving beyond the well-mixed assumption. Thus, the aim of the doctoral project is to further develop key technical aspects of a modelling framework initiated by the academic and industrial supervisors, in particular considering the eye as a spatially distributed system, rather than as a compartmentalised one.

The objective of initial studies will be to utilise a mixed effects framework for model selection and the systematic estimation of parameters in spatially distributed models which, in turn, will be used to assist the interpretation of nonclinical data. Further studies will continue to pursue the aim of developing the modelling framework, for example with the objective of incorporating retinal penetration of prospective therapeutics and analysing formulations intended to reduce excessive retention at the site of injection. A final objective will be to investigate novel drug and biologic designs, including developing rational predictions for testable improvements.

 

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