Improving hematopoietic cell transplantation therapeutics:emphasis in pharmacokinetic-pharmacodynamic relationships and pharmacogenomics.

Abstract

Treatment-related mortality and acute graft vs host disease remain prominent clinical problems in nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). Hence, the need for improved preparative regimens and immunosuppressive strategies in HCT persists. The research presented in my dissertation will be focused on defining pharmacokinetic-pharmacodynamic relationships, and pharmacogenomics involving two antineoplastic agents, fludarabine and clofarabine, and the immunosuppressive agent, mycophenolate all of which are used in the setting of HCT. Fludarabine is a purine analog commonly used in both adult and pediatric nonmyeloablative allogeneic HCT. Although the pharmacokinetics of fludarabine have been extensively studied in a variety of malignant diseases, very little data is available in nonmyeloablative HCT and the relationship between fludarabine pharmacokinetic parameters and clinical outcomes such as treatment-related mortality have yet to be evaluated. Similarly, no PK data is available for clofarabine; a newer purine analog currently used pediatric patients undergoing HCT for non-hematologic malignancies. Finally, mycophenolic acid pharmacokinetics in HCT recipients displays wide inter- and intra-patient variability in plasma concentrations and low mycophenolate exposure is associated with lower rates of engraftment and greater risk of acute graft vs host disease. Patient characteristics such as weight or body surface area, or clinical markers for hepatic and renal function incompletely explain pharmacokinetic variability suggesting there may be genetic factors influencing mycophenolate metabolism or transport. The methodologies and techniques employed to evaluate each individual agent will differ, including pharmacokinetic and statistical analyses. However, all projects share the common goal of improving patient outcomes and reducing toxicity in this very complex patient population.