Relationship Between Intravenous Busulfan Pharmacokinetics and Patient Characteristics in Allogeneic Stem Cell Transplant

Background: Busulfan is an alkylating agent commonly used for myeloablation in hematopoietic stem cell transplantation (SCT). Narrow therapeutic index and 2-3 fold interpatient PK variability underscores the need to further explore predictors of busulfan clearance.  This analysis aimed to predict the percentage of patients who were within the targeted AUC range of 4800 µM*min with dosing strategies based on actual body weight (ABW) or adjusted body weight (AdBW, and to determine patient characteristics that may impact busulfan clearance.

Methods: This retrospective analysis assessed allogeneic SCT patients who received a test dose of 0.8 mg/kg IV busulfan, dosed by AdBW, prior to conditioning therapy containing therapeutically dosed busulfan.  All patients were treated between June 2004 and July 2013 at the University of North Carolina at Chapel Hill.  Noncompartmental PK parameters were calculated from this test dose using Phoenix™ WinNonlin®Pharsight software. Measured PK data were obtained from test the test dose and used to extrapolate an AUC for ABW and AdBW. Acceptable AUCs were within 15% of the targeted of 4800 µM*min.

A linear model with log of busulfan test dose clearance as an outcome and patient characteristics that included disease state, bone marrow donor type, gender, race, ethnicity, body surface area (BSA), anticonvulsant prophylaxis used (levetiracetam or phenytoin), total bilirubin and serum creatinine was fit.

Results: The study reviewed a total of 102 patients with a mean age of 40.3 (range 18 to 63). The analysis included 63 males, 87 Caucasians, and 5 African Americans. Seizure prophylaxis with levetiracetam was given to 41 patients, and 51 patients received phenytoin. Based extrapolated PK data, 42% of patients dosed by ABW were within targeted AUC range, versus 47% of patients dosed by AdBW.

After adjusting for patient characteristics, a unit increase in BSA was associated with 0.68 (p = < 0.001) increase in busulfan log(clearance). Although not statistically significant, African American race was associated with a trend towards decreased clearance (p = 0.064). No correlation was seen for age (p = 0.226), gender (p = 0.417337), or for any other variable that was assessed.  

Discussion: Weight-based busulfan dosing using AdBW or ABW each results in <50% of patients being achieving a goal AUC of 4800 µM*min. Interpatient variability of IV busulfan may be partially explained by BSA, yet differences in race, gender, and age did not correlate busulfan clearance. These data suggest that other dosing strategies, such as PK-guided dosing, may help to minimize over/under dosing and to overcome interpatient variability.