229: Twice-Daily Intravenous (IV) Busulfan (Bu) x 4 Days in Children Undergoing a Reduced-Intensity Conditioning (RIC) Regimen with Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT) is Safe and Well-Tolerated but Results in Significantly Increased Bu Clearance (CL) and Decreased Area Under the Curve (AUC) and Half-Life (t1/2) When Compared to IV Bu Twice-Daily Dosing Pharmacokinetics (PK) in Adults

Inaccurate Bu dosing during HSCT conditioning can result in increased graft failure or excessive regimen-related toxicity. IV Bu is safe and effective in pediatric HSCT recipients at a dose of 4 mg/kg/day (≤4 yr) or 3.2 mg/kg/day (>4 yr) using q6 h × 16 dosing but Bu PK is age-dependent (Wall, Blood, 2000a). Q12 h × 8 dosing has been shown to be safe and effective in adults, with mean first-dose AUC 3576 mmol∗min, t1/2 3.46 h and CL 1.88 ml/min/kg (Fernandez, BBMT, 2002). However, Bu safety and PK data is lacking for q12 h × 8 dosing in pediatric HSCT recipients. We studied 15 pediatric pts, mean age 9.5 yr (1.4–20.9 yr) with malignant (n = 5) and nonmalignant (n = 10) conditions who underwent RIC for alloHSCT with IV Bu q12 h × 8 dosing (4 mg/kg/day [< 4 yr]; 3.2 mg/kg/day [≥4 yr]), fludarabine (30 mg/m2/day × 5 days) and alemtuzumab (54 mg/m2/5 days). Phenytoin/fosphenytoin load was given prior to start of Bu; maintenance continued 48 h post-Bu. Donor sources were: 3 6/6 & 1 5/6 matched-related donor, 1 10/10, 2 9/10 & 2 8/10 MUD, 2 6/6 related cord blood (CB) and 4 4/6 unrelated CB. PK samples (n = 12) were obtained at hr 1, 2, 3, 5, 6, 7 and 8 after start of 1st dose. Bu levels were measured by a GC-MS method on heparinized plasma. Results are summarized in Table I. Target Css was 600–900 ng/ml. 5 pts required dose increases; 1 was dose-reduced. Mean CL (ml/min/kg) for <4 yr (n = 3) was significantly higher than in ≥4 yr (4.59 ± 0.52 v 3.45 ± 0.72, p = .0326). Difference between mean Bu t1/2 for <4 yr v ≥4 yr trended toward but did not reach significance (1.94 h ± 0.46 v 2.57 h ± 0.59, p = 0.13). 2 pts (13%) had seizures unrelated to Bu; there was no VOD. Donor chimerism was 80% at D + 30 (n = 13) and 90% at D + 60 (n = 11). 1 of 15 pts had primary graft failure; this pt also had the 2nd highest Bu CL (4.77 ml/min/kg), lowest t1/2 (1.62 h) and 2nd lowest AUC (1648 mmol∗min). In summary, we demonstrated significantly lower AUC and t1/2 and significantly increased CL when compared to adult q12h dosing PK data, suggesting that q12h IV Bu PK may depend on patient age (Table I). We also found a significant age-dependent (<4 yr v ≥4 yr) difference in Bu CL, possibly due to increased glutathione-S-transferase activity (Gibbs, Drug Metab Dispos, 1999). Furthermore, we showed that q12h IV Bu in pediatric pts results in low toxicity and high engraftment post-RIC regimen. Additional pediatric subjects are needed to determine if increased Bu CL and decreased AUC result in increased risk of graft failure.Tabled 1Busulfan pharmacokinetic data for q12 hour dosing in pediatric and adult patientsAUC mmol∗min (mean ± SD)t½, hr (mean ± SD)CL, ml/min/kg (mean ± SD)Vd, L (mean ± SD)Css ng/ml (mean ± SD)Pediatric (n = 12; n = 11 for AUC & VD1900 ± 3832.41 ± 0.613.74 ± 0.8322.8 ± 14.6653 ± 125Adult (n = 6) (Fernandez, BBMT, 2002)3576 ± 7403.46 ± 0.381.88 ± 0.37Not ReportedNot Reportedp-valuep