Intravenous (i.v.) or Oral (os) Busulphan (BUS) in Children Prior to Autologous (Auto) or Allogeneic (Allo) Stem Cell Transplantation (SCT): Pharmacokinetics (PK), Toxicity and Compliance.

Introduction: High dose BUS is an important component of pre-transplant conditioning regimen in children with advanced hematological malignancies or solid tumor undergoing allogeneic or autologous stem cell transplantation. Variable intra and inter systemic drug exposure as measured by area under curve (AUC), can occurs following oral administration and may be influenced by age, body weight, absorption variability and, particularly in infants, by difficulties to assumption.

Aims: to compare the PK, the toxicity and the compliance of iv versus oral BUS administration in children undergoing pre-transplant conditioning regimen.

Patients and methods: 12 patients (pts), median age 37 (7–177) mos, body weight 6–69 kg, affected by AML (3), ALL (4), NB (3), Thalassemia (2), undergoing to autoSCT (4) or alloSCT (8), received as preparative regimen oral BUS at the dose of 1 mg/kg every 6 hours for a total of 16 doses (6 pts, GR1), or 2 hours i.v. infusion of BUS at the dose of 0.8 mg/kg every 6 hours for a total of 16 doses (6 pts, GR2). Four out of 6 GR1 pts (7–30 mos) had a nasogastric radiolus to allow BUS assumption. PK studies were performed after the first dose of BUS on blood samples collected at 0, 1, 2, 4, 6 hours after first administration in GR1 and at 0, 2, 3, 4, 6 hours from the beginning of the first infusion in GR2. BUS plasma level was determined by high-performance liquid chromatography as described by Henner et al.

Results: GR were comparable as for age (p= 0.07) and body weight (p= 0.14). Comparison of PK median values (+SD) in GR1 versus GR2 didn’t highlighted statistically significant differences as for AUC (p= 0.20) and for T1/2 (p= 0.11). Peak concentration was higher in GR2 (p= 0.058). Bioavailability was 0.61. Variation factor (VF%) were constantly low in GR2. No pt showed acute or late treatment-related extra-medullary toxicity and all pts developed a rapid and sustained hematopoietic recovery.

Conclusions: systemic exposure to 0.8 mg/kg iv BUS versus 1 mg/kg oral BUS is overlapping. Low VF% highlight a smaller interpatient variability in exposure compared to oral BUS. Moreover allows to avoid assumption difficulties in younger pts.