INTRAVENOUS (IV) BUSULFAN (BU) ADMINISTERED TWICE DAILY DURING CONDITIONING PRIOR TO ALLOGENEIC STEM CELL TRANSPLANT (ALLOSCT) IN PEDIATRIC RECIPIENTS HAS SIGNIFICANTLY DIFFERENT HALF-LIFE OF ELIMINATION AND CLEARANCE IN RECIPIENTS > 4 YEARS AND THOSE <= 4 YEARS

Bu is a drug used in conditioning prior to AlloSCT with a narrow therapeutic window. High Bu exposure can lead to veno-occlusive disease, while low Bu exposure can result in graft failure. Every 6 hr IV Bu has been shown to be safe and effective at a dose of 4.0 mg/kg/day ≤4 years; 3.2 mg/kg/day >4 years. Age-based dosing adjustments are suggested due to increased Bu metabolism in the very young. However, data comparing the pharmacokinetic (PK) parameters in IV q12 hr Bu regimens between these age groups is lacking. We compared the PK parameters of a cohort of pediatric AlloSCT recipients receiving IV Bu q12 hr 2 mg/kg/dose ≤4 years (1.6 mg/kg/dose >4 years) stratified by age group. Blood was collected at 1, 2, 3, 5, 6, 7 and 8 hrs after the start of first Bu infusion for concentration analysis. Bu PK parameters of area under the curve (AUC), volume of distribution (Vd) and elimination constant (kel) were estimated by a single compartment first order elimination model. The secondary PK parameter of Bu clearance (CL) was calculated using the formula CLBu = Vd * kel. Both Vd and CL were normalized (CLn) as a ratio to patient weight. The half-life (t1/2) was calculated as 0.693/kel. The steady state concentration (Css) was computed by dividing AUC by the dosing interval. The cohort of 49 IV Bu q12 hr recipients was age stratified into pediatric recipients ≤4 years (n = 18) vs. >4 years (< 19 years [n = 31]). In ≤4 years vs. >4 years recipients normalized Vd was comparable (0.68 ± 0.10 vs. 0.70 ± 0.04 L/kg, p = 0.594). However, significant differences were seen in PK parameters of elimination: t1/2 (115 ± 21 vs. 146 ± 16 min, p = 0.008) and CLn (4.4 ± 1.05 vs. 3.5 ± 0.4 ml/min/kg, p = 0.038). (Table 1) Despite these differences in t1/2 and CLn between age groups Css analyses (700 ± 115 vs. 679 ± 77 ng/ml, p = 0.702) showed no statistically significant differences. Targeted Bu Css was achieved in 61% of recipients ≤4 years, and 55% of those >4 years. (p = 0.669) The significant difference in Cln and t1/2 emphasizes the underlying Bu metabolism differences between age groups. One known cause is the increased activity of glutathione-S-transferase in young children. The age-based dosing adjustment built into the study demonstrates merit through comparable Bu Css in both age groups. In summary, q12 hr IV Bu recipients ≤4 vs. >4 years have different Bu PK, but achieve comparable Bu exposure with an aged-based dosing adjustment.Table 1IV Bu q12 hr Pharmacokinetics Stratified by AgeAge Group≤ 4 years> 4 yearspn = 18n = 31Mean95% CIMean95%CIAge (years)2.01.4-2.610.58.6-12.4<0.001Weight (kg)12.110.3-14.033.226.7-39.7<0.001Dose (mg/kg)2.02.0-2.01.61.6-1.6<0.001Volume of Distribution (L)0.680.58-0.780.700.66-0.740.594Half-life (min)11594-136146130-1620.008Clearance (ml/min/kg)4.43.3-5.43.53.1-3.90.038AUC (mmol∗min/L)20471709-238519841757-22110.702AUC/Day (mmol∗min/L)40943418-477139683515-44220.702Css (ng/ml)700585-816679601-7560.702 Open table in a new tab