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Title: Mathematical modelling of drug-ion channel interactions for cardiac safety assessment
Author: Beattie, Kylie Ann
ISNI:       0000 0004 6062 6902
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Unintended drug interactions with ion channels in cardiac cells can alter normal electrical activity in the heart. This can lead to the onset of cardiac arrhythmias which can be potentially fatal. Such arrhythmias are a leading cause of market withdrawal of pharmaceutical compounds. It is therefore important for pharmaceutical companies to identify drugs which may cause adverse changes to cardiac electrical activity as early as possible in the drug development process. Computational approaches provide great potential for assessing cardiac safety at low cost and high-throughput. Regulatory guidelines for the assessment of cardiac safety are being revised and computational approaches are envisaged to form an integral part of future guidelines. It is therefore important that computational methods proposed for use are both accurate and well validated. This thesis is focused around the use of mathematical models for cardiac safety assessment. We evaluate an approach which uses information on the extent of drug block of cardiac ion channels to predict changes in cardiac electrical activity in a rabbit-based safety test. A possible limitation of this approach is the representation of drug-ion channel interactions within the mathematical model. We go on to explore the representation of the kinetics of the cardiac potassium channel encoded by hERG (human-Ether-a-go-go Related Gene) within mathematical cardiac electrophysiology models. We demonstrate how existing mathematical models of hERG channel kinetics can behave very differently when used to simulate the same voltage protocol. We also show the impact that the choice of hERG channel representation used within an action potential model can have on the prediction of drug effects on cardiac activity. We design and perform novel experiments to allow us to construct and validate mathematical models describing hERG channel kinetics. We demonstrate the potential for the use of computational approaches in cardiac safety assessment. However, at the same time we indicate that models used for this purpose must be carefully constructed and thoroughly validated, as well as illustrating ways this may be achieved. Such considerations are a prerequisite for more predictive computational assessment of cardiac safety.
Supervisor: Mirams, Gary ; Gavaghan, David ; Louttit, James Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available