Pharmacokinetics (PK) of intravenous (IV) busulfan (BU) in pediatric patients

Highly variable BU disposition in pediatric patients receiving high dose chemotherapy for stem cell transplant contributes to toxicity and engraftment failure. To minimize PK variability, a study of an investigational IV BU formulation and individualized dose regimens to achieve target concentrations (TC) was done in 15 children (median age 3 yrs). Initial BU dose was 37.5 mg/m² Q6H*4 days (D). BU concentrations (n=6) were measured by GC-MS on Dl and D4 with limited samples (n=3) on D2 and D3, clearance (CL) estimated, and doses adjusted to TC. D1 median (range) CL 1/hr/m2 was 6.27 (2.33-9.20) (n=15) and increased to 7.26 (4.38-14.14) on D4 patients studied (n=11; median change 21%). Adjusted doses to achieve TC were 20.4-46.2 mg/m². Median CL was higher (p<0.05) in younger (7.67;<3 yrs) than older (5.15;>3 yrs) children. Median D4 dose is 50% higher than the usual adult dose of 1 mg/kg. IV BU was well tolerated and provides consistent concentrations within subjects but PK variability requires individualized doses to account for the effect of age and induction on BU metabolism.