Variation in prescribing patterns and therapeutic drug monitoring of intravenous busulfan in pediatric hematopoietic cell transplant recipients

Abstract

Personalizing intravenous (IV) busulfan doses in children using therapeutic drug monitoring (TDM) is an integral component of hematopoietic cell transplant. The authors sought to characterize initial dosing and TDM of IV busulfan, along with factors associated with busulfan clearance, in 729 children who underwent busulfan TDM from December 2005 to December 2008. The initial IV busulfan dose in children weighing ≤12 kg ranged 4.8-fold, with only 19% prescribed the package insert dose of 1.1 mg/kg. In those children weighing >12 kg, the initial dose ranged 5.4-fold, and 79% were prescribed the package insert dose. The initial busulfan dose achieved the target exposure in only 24.3% of children. A wide range of busulfan exposures were targeted for children with the same disease (eg, 39 target busulfan exposures for the 264 children diagnosed with acute myeloid leukemia). Considerable heterogeneity exists regarding when TDM is conducted and the number of pharmacokinetic samples obtained. Busulfan clearance varied by age and dosing frequency but not by underlying disease. The authors- group is currently evaluating how using population pharmacokinetics to optimize initial busulfan dose and TDM (eg, limited sampling schedule in conjunction with maximum a posteriori Bayesian estimation) may affect clinical outcomes in children.

Figure 1

Association of age with IV busulfan clearance expressed by dosing body weight, unadjusted for dosing frequency (A) and its partial residuals adjusted for dosing frequency (B). Dashed lines are 95% confidence band.

Figure 2

Association of age with IV busulfan clearance expressed by BSA, unadjusted for dosing frequency and diagnosis (A) and its partial residuals adjusted for dosing frequency and diagnosis (B). Dashed lines are 95% confidence band.

Figure 3

Detrended normal plot of randomized quantile residuals with confidence band. Residuals all lie within the band indicating no evidence of lack of fit of the regression model.

Figure 4

Simulated busulfan plasma concentrations in a 1-year-old infant (top) and 11-year-old child (bottom) receiving IV busulfan at doses of 0.45 and 2.17 mg/kg. Pediatric population pharmacokinetic model modified from adult population pharmacokinetics.