Takahashi, Takuto2022-11-142022-11-142022-08https://hdl.handle.net/11299/243098University of Minnesota Ph.D. dissertation. August 2022. Major: Experimental & Clinical Pharmacology. Advisor: Mark Kirstein. 1 computer file (PDF); vi, 149 pages.Hematopoietic cell transplantation (HCT) is a high-risk therapeutic procedure that is reserved for patients, whose disease is either refractory or incurable by other measures. Conditioning therapy is an important first step in HCT with multiple purposes (i.e., treat refractory malignancy, ablate bone marrow to make physical space, and suppress host immune rejection). Conditioning therapy often entails high-dose cytotoxic chemotherapy, and the resultant high toxicity allows only a narrow therapeutic window, and either under- or over-exposure to these agents can result in detrimental consequences. When the cost of therapeutic failure is very high, as in HCT patients, a minor adjustment in dosing can have a clinically significant impact on patient outcomes. Population pharmacokinetic modeling approach enables delineation of dose-exposure relationship by identification of covariate effects within a patient population. One potentially critical covariate is germline genetic variation that may influence the pharmacokinetic-pharmacodynamic genes of drugs. In this thesis, I studied the individualization of dosing in commonly used drugs in HCT including busulfan, voriconazole, and cyclophosphamide. The studies presented in this thesis attempted to generate new knowledge that would improve drug utilization through dosing individualization. Although proper validation is needed, each of the studies has the potential to directly improve patient outcomes. An important knowledge, gained through the literature, is that conventional dose identification studies utilized in the field tend to test oversimplified dosing regimens (i.e., one-size-fits-all approach), which likely insufficiently accommodate the complexity in the pharmacokinetic-pharmacodynamic variabilities in HCT setting.enbone marrow transplantationhematopoietic cell transplantationpharmacogenomicspharmacometricspopulation pharmacokineticThesis or Dissertation