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Title: Structural and statistical aspects in joint modelling of artesunate pharmacometrics and malarial parasite lifecycle
Author: Hall, Adam J.
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2015
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Malaria is a parasite with a complex lifecycle, and commonly used antimalarial agents from the artemisinin family have varied effectiveness over different stages of this lifecycle. The pharmacokinetic profile of the artemisinins is also strongly influenced by the parasite burden and lifecycle stage. This work introduces a new pharmacokinetic and pharmacodynamic model incorporating these interdependent drug and lifecycle features, for orally administered artesunate and its principal metabolite dihydroartemisinin. This model, like the underlying system whose features it attempts to capture, is quite complex and cannot be solved analytically like standard linear first-order compartmental models previously used for pharmacokinetic modelling of these drugs. Therefore, understanding, inference and validity are explored through use of the modern statistical technique of a Sequential Monte Carlo sampler. Structural, numerical and practical identifiability are important concepts for all models, the latter two especially so in this case as the model structure does not admit an algebraic structural identifiability analysis. Motivated by this, the above identifiability concepts are also investigated in connection with the Sequential Monte Carlo technique. Sequential Monte Carlo is demonstrated to be a useful tool for gaining insight into models whose structural identifiability is not known, just as it is also shown to have significant advantages in parameter inference over the classical approach. The coupled parasite lifecycle and artemisinin-derivative model is built in stages, starting with an in vitro submodel capturing the dynamics of uptake of artemisinins into parasitised and non-parasitised red blood cells. Next, the parasite lifecycle, or ‘ageing’ model, is introduced, which uses a new concept of shadow compartments to achieve its aims of describing ageing in continuous time and to exhibit sufficient control over the parasite population. Finally, these models are integrated together into the full coupled pharmacokinetic and pharmacodynamic model. More work is needed to fully assess the resultant model on clinical datasets, but the building blocks upon which it was constructed appear to fulfil their aims reasonably well.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QA Mathematics ; RC Internal medicine