Utilization of a Population Pharmacokinetic Model to Improve a Busulfan Test-Dose Strategy in Allogeneic Hematopoietic Cell Transplant Recipients.

Abstract

Busulfan is an alkylating agent used as part of conditioning chemotherapy regimens prior to allogeneic hematopoietic cell transplant (allo-HCT). Pharmacokinetic (PK)-guided test-dose strategies have been shown to improve the number of patients achieving busulfan exposure goals and improve clinical outcomes. However, current practices require extensive PK sampling. In this study, PK data were retrospectively collected from busulfan drug monitoring records from adult allo-HCT recipients who received once-daily intravenous busulfan at the University of North Carolina Medical Center (UNCMC). A population pharmacokinetic (popPK) model was developed to identify sources of interindividual variability and evaluate alternative PK sampling strategies. A 2-compartment model, with covariate effects of actual body weight and sex, best described the data. The typical value of clearance for an 83kg male was estimated to be 11.21L/h. Fifty-nine percent of allo-HCT recipients were estimated to have met the UNCMC institutional myeloablative conditioning (MAC) exposure goal based on model post hoc estimates of clearance using all PK samples obtained following MAC dosing. Fifty-seven percent of patients were estimated to have met this goal based on post hoc estimates using a single PK sample. Our results indicate once-daily, intravenous busulfan PK in adult allo-HCT recipients receiving MAC dosing can be reasonably described by a popPK model, and the use of a sparse PK sampling strategy may be feasible for determining target exposure attainment following MAC dosing. Use of a popPK model and sparse PK sampling strategy to carry out busulfan test-dose procedures could reduce health care costs and inconvenience to patients.