Evaluating pharmacokinetics and pharmacodynamics of intravenous busulfan in pediatric patients receiving bone marrow transplantation

Abstract

BU is a commonly used conditioning agent in BMT. However, it is a narrow therapeutic index drug which shows a strong correlation between AUC and both efficacy and toxicity. Studies in pediatric patients have suggested that children less than four yr of age have a greater clearance and thus lower AUC at standard adult doses. The goal of this retrospective analysis was to evaluate any age-related pharmacokinetic and pharmacodynamic differences in pediatric patients who received BU as a conditioning agent. From 2003 to 2006, 21/77 pediatric patients who received BMT were reviewed. There were 15 males and six females with a mean age of six yr old. Diagnoses of leukemia (n = 11), Hodgkin's lymphoma (n = 3), myelodysplastic syndrome (n = 2), and other (n = 5) were included. Sixteen patients received BU + cyclophosphamide while five patients received BU + another agent. There were 20 allogeneic and one autologous transplants among which 16 were human leukocyte antigen matched and five were mismatched. Average BU clearance in patients younger than four yr old (n = 8) was 4.1 +/- 1.0 mL/min/kg vs. 3.1 +/- 0.7 mL/min/kg in patients older than four yr old (n = 13) (p = 0.02). The corresponding averages for AUC were 998 +/- 226 microm x min vs. 1155 +/- 183 microm x min (p = 0.12). No patients younger than four yr old developed VOD while five of the older patients did (p = 0.044). There were no significant differences in terms of engraftment and acute GvHD. There were significant age-related pharmacokinetic differences in pediatric patients less than four yr of age receiving BU for conditioning prior to BMT. There was a decrease in drug toxicity seen in these patients.