title: Pharmacological modelling to investigate antimalarial drug treatment
Creators: name: Kay, Katherine
Publisher: name: University of Liverpool Repository
Year: 2014

description: Malaria remains a major public health concern for billions of people worldwide. Achieving the ambitious goal of malaria eradication requires co-ordination of control strategies dealing with a range of parasite, vector, human, social and environmental factors. Availability of effective antimalarial treatment is a key component in malaria control. However the number of drugs available is limited and drug resistance, particularly in Plasmodium falciparum, has now been reported for all currently available antimalarials. Mathematical models provide the opportunity to explore key features underlying antimalarial drug action, effectiveness and resistance. They further allow investigation into questions that cannot otherwise be easily addressed, either because they are too expensive, unethical or logistically too complex. This thesis aims to develop pharmacological models to investigate antimalarial drug treatment. In Chapter 2 we develop a pharmacokinetic-pharmacodynamic (PK/PD) model of antimalarial drug treatment (calibrated using published data) and use it to investigate the efficacy of artemisinin combination therapies (ACTs). Chapter 3 addresses two assumptions built into the methodology that limit the models future application. The model now allows for (i) time lags and drug concentration profiles for drugs absorbed across the gut wall and, if necessary, converted to another active form (ii) multiple drugs within a treatment regimen (iii) differing modes of drug action in combinations (iv) modelling drugs converted to an active metabolite with similar modes of action. In Chapter 4 we extend the methodology to allow for i) the presence of more than one clone when treatment begins (ii) the acquisition of new clones during treatment follow-up (iii) the tracking of individual clones using molecular markers. We then use these extensions to simulate clinical trial data to determine the best methods of analysis. Chapter 5 details how the drug action components of the extended PK/PD model were incorporated into OpenMalaria; a mathematical model of malaria epidemiology allowing investigation of the effects of various intervention strategies including malaria vaccines, vector control strategies and antimalarial drug treatment. In Chapter 6 we investigate the ability of clinical trials to accurately estimate (WoS) using the extended PK/PD model. Windows of selection (WoS) are often used to quantify the genetic process whereby parasites evolve increasing tolerance to antimalarial drugs. We noted a conspicuous lack of comprehensive, good-quality PK datasets currently available in the literature. Despite this, the models produced results highly consistent with field data. They were applied to investigate the potential implications of drug resistance and to make predications about the future effectiveness of antimalarials. We emphasise the value of mathematical models by simulating ‘field data’ to assess the best methods of analysing clinical trials and to investigate the predictive ability of WoS. While we do not suggest models can replace the information gained in clinical trials, this work does demonstrate the importance of mathematical models capable of generating results consistent with field data.