Variable drug response and lack of information on drug disposition and action in rare diseases are challenges that need to be addressed for safe and effective provision of medicines. The main aim of work presented in this thesis was to address these challenges in selected areas of liver disease in children. Population pharmacokinetic and pharmacogenetic analyses in children with liver transplant revealed that tacrolimus apparent clearance decreased over time, and was higher in carriers of the CYP3A5*1 allele in both donors and recipients, however, the recipient genotype showed a more profound impact. A sub-analysis in CYP3A5 non-expresser recipients, revealed that tacrolimus clearance in this subpopulation was higher in carriers of the POR*28 allele. When compared to liver transplant patients, children with intestinal transplant exhibited higher tacrolimus clearance. Several genetic variations were investigated for correlation with phannacodynamic outcomes; of these, the IL-4 -590 C allele showed a trend towards association with acute rejection in intestinal transplant patients, while selected ABCB1 SNPs at 6 months post-transplant were associated with tacrolimus associated nephrotoxicity only in liver transplant patients. Data on the use of nitisinone for treatment of tyrosinemia type I in children, revealed that, compared to dietary treatment alone, the use of this agent is associated with enhanced patient survival and decreased need for transplant, especially if the therapy is initiated early after birth. A distinct α-fetoprotein profile was noted in children who developed hepatic cancers. The population pharmacokinetics of nitisinone was evaluated for the first time in the UK population and a gradual time dependent decrease in nitisinone clearance was observed over a period of five years. A secondary aim of the present thesis was to analyse the content, quality and trends of reporting of issues relating to liver/intestinal transplantation in UK and USA newspapers. The newspaper coverage of this topic was generally poor in quantity and in quality. The general slant regarding transplantation and donation was positive, but few articles provided information regarding the means through which an individual could become a donor. In general the current research demonstrated the usefulness of population approaches in analysing the pharmacokinetics of drugs prescribed to children and the role of genetics in variable pharmacokinetic and pharmacodynamic outcomes of narrow therapeutic index drugs such as tacrolimus.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:675938 |
| Date | January 2014 |
| Creators | Abdel Jalil, Mariam Hantash |
| Publisher | Queen's University Belfast |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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