Pharmacogenetics Kinetics and Dynamics of Drugs used in Stem Cell Transplantation

Abstract

This doctoral work has comprehensively evaluated the pharmacokinetics and pharmacogenetics of Busulfan and cyclophosphamide used for conditioning patients with thalassaemia undergoing HSCT and evaluated their impact on clinical outcome. To the best of our knowledge, this is the first study which has shown the inter-relationship between busulfan metabolism and CEPM the reporter molecule of Cy biotransformation and SOS. This is the first study that has looked at the pharmacokinetics of these two drugs when they are combined with fludarabine in a reduced intensity conditioning regimen for HSCT in thalassaemia. Wide inter and intra individual variations in systemic exposure to busulfan and cyclophosphamide partly related to pharmacogenetic polymorphisms, suggest the need for targeted dose adjustment. GSTM1 deletion is a significant risk factor for the development of SOS. SNPs in CYP2B6 gene, an important predictor of cyclophosphamide pharmacokinetics. Therefore genotyping all the patients before SCT for GST and CYP450 polymorphisms would help in identifying the slow and rapid metabolizers. Trough level of Busulfan and decreased systemic exposure to Cy and its metabolites predicts graft rejection. Significant associations between the levels of busulfan and CEPM in relation to toxicity suggests that Bu or its metabolites cause hepatic toxicity that may be worsened by subsequent exposure to Cy, resulting in SOS. Toxicity was reduced with Fludarabine based conditioning probably because of lower doses of busulfan and cyclophosphamide and the one day gap between Bu and Cy. This suggests that this would be a good regime to use for patients in Class II but the increased rejection in Class III patients suggests that reduced systemic exposure was not enough to ensure engraftment. To conclude, pharmacokinetics and pharmacogenetics of Bu and Cy will help predict treatment outcome with reference to both toxicity and graft rejection. newline