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Title: Application of pharmacokinetics and pharmacogenomics to tailor anti-cancer and immunosuppressive therapy
Author: Hawwa, Ahmed Fayeq
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2004
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Abstract:
In the research presented in this thesis, the application of pharmacokinetic principles and pharmacogenetic tools to enhance therapeutic drug monitoring of the anti-cancer and immunosuppressive medications (6-MP and AZA) in two patient populations (paediatric patients with ALL and adults with IBD) was investigated. Before a pharmacokinetic analysis was conducted, a valid and reliable microanalytical method for the rapid, simultaneous and accurate determination of 6-MP and four of its metabolites from small volumes (200JlL) of plasma and erythrocytes was developed (Chapter 2). The developed method was successfully applied to the analysis of 75 samples from 19 paediatric patients with ALL and 44 samples from 35 adult patients with IBD. The association between the measured metabolite levels and the ·allelic variations of 3 enzymes involved in 6-MP metabolism (XO, TPMT and ITPA) was examined (Chapter 3). In addition, the association between the studied variants and the occurrence of myelotoxicity and haematological parameters was evaluated. This contributed to a clearer understanding of 6-MP metabolism and showed important pharmacogenetic associations. Furthermore, it threw light on potential genetic. characteristics that may contribute to higher risk of adverse events. In Chapter 4, the individual relationships between 6-MP and its metabolites and the correlations between these metabolites and dose, haematological parameters or the incidence of various forms of myelotoxicity in ALL and IBD patients were evaluated. The intra- and inter-patient variability in 6~MP metabolite concentrations were utilised to investigate the different factors that could lead to this variation via constructing a population pharmacokinetic model from the metabolite concentrations measured. The model offered a more rational dosing approach than the traditional empirical method since it combin~d the current practice of using body surface area in 6-MP dosing with a pharmacogenetically guided dosing based on TPMT genotype. In Chapter 5, adherence to 6-MP/AZA in ALL and IBD patients was evaluated via examining red blood cell and plasma levels of drug and metabolites. In addition, adherence questionnaires completed by patients or their parents (in case of children) and therapeutic outcome measures (as assessed by haematological parameters, myelotoxicity or activity indices) were used to assess adherence in the same cohort of patients. The study demonstrated non-adherence to medication in both ALL and IBD populations and highlighted the need for programmes to help these patients better !lndefstand their disease and for the implementation of disease-specific interventions to improve medication adherence.
Supervisor: Not available Sponsor: Not available
Qualification Name: Queen's University Belfast, 2004 Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.486218  DOI: Not available
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