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Title: Safe and effective use of medicine in children : adherence and population pharmacokinetic approaches
Author: Alsous, Mervat Musbah Zaki
ISNI:       0000 0004 5369 0981
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2014
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Safe and effective use of medicines is an important issue especially in children with chronic illness who are less resilient to adverse events and in whom disease progression may not be addressed if appropriate medication is not taken. The research programme presented in this thesis focused on the use of dried blood spot (DBS) sampling in the assessment of adherence and population pharmacokinetics (PK) of medicines in children. The first aspect of the research focused on the use of azathioprine/6- mercaptopurine (AZA/6-MP) for the treatment of children with Inflammatory Bowel disease (IBD). Portraying IBD and its treatments by the newspaper media in the UK and USA, as·a source of information and advice to the public, was investigated. Research demonstrated that information about IBD and its treatment was not frequently mentioned and reporting was generally of low quality. The media may impact public beliefs and concerns about medications and in turn influence how they use medicines themselves and give them to their children. Assay methods for the quantification of AZA/6-MP metabolites (as an adherence measure} in packed RBCs and plasma (using HPLC) and in dried blood spots (using LC/MS/MS) were developed and validated. The Bland-Altman test indicated equivalence in determined concentrations of AZA/6-MP metabolites in packed red blood cells and DBS samples. These assays were applied successfully, as part of a multi-method approach, to assess adherence to AZA/6-MP in a pilot study in children with IBD, including home DBS samples collected by children or their parents. The overall adherence rate using this method, coupled with other objective and subjective measures, was determined to be 71 %. The return rate of home DBS was reasonably high (81 .0%), however, more training on the proper use of the calibrated capillary used to collect home samples is required to help ensure good quality samples. Child concerns about medicines and the presence of side-effects, were found to significantly decrease the probability of the patient being adherent. The second major piece of clinical research presented in this thesis involved the development of a pharmacokinetic model for ketamine when used for procedural sedation and anaesthesia in neonatal intensive care patients. An LC-MS/MS method was developed, validated and applied effectively to the quantification of ketamine and norketamine enantiomers in dried blood spot samples collected from neonates recruited into the clinical trial. Utilising the data generated from the work, pharmacokinetic parameters were estimated for this patient group using population pharmacokinetic modelling. A lower volume of distribution and a shorter half-life for both ketamine enantiomers, compared to published data for older children and adults, were found. Weight was found to be the only covariate with a significant influence on the PK parameters. With further refinement, the final pharmacokinetic models can be utilised when designing ketamine dosage regimen in neonates. The research presented in this thesis clearly demonstrated the utility of the novel DBS approach which has extended the scope for conducting adherence and population pharmacokinetic studies in children.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available