title: Target dose adjustment of busulfan in pediatric patients undergoing bone marrow transplantation.
abstract: Published data suggest that the average concentration of busulfan at steady state (Bu Css) is critical for successful engraftment in children receiving busulfan as a conditioning agent for bone marrow transplantation (BMT). We previously found in children that a Bu Css <600 ng/ml correlated with autologous recovery/mixed chimerism; there was no correlation between Bu Css and regimen-related toxicity (RRT). In a cohort continuous with the previous trial, we prospectively evaluated targeted busulfan concentrations in 32 pediatric patients (age 0.6-18.5 years) with AML (n = 6), CML (n = 6) and non-malignant disorders (n = 20) receiving HLA-closely matched donor grafts. In this trial, individual busulfan pharmacokinetics were performed prior to admission. Busulfan doses were then adjusted to achieve a Bu Css target range of 600-900 ng/ml +/- 10% depending on donor source and disease. A repeat study was done following dose 1 of the conditioning regimen. Thirty of thirty-two (94%) patients achieved target concentrations. Total busulfan doses ranged from 10.9 to 29 mg/kg. Thirty of thirty-two patients (94%) have durably engrafted. Grade 3/4 RRT occurred in seven patients (21%). Targeting Bu Css ranges of 600-900 ng/ml significantly improved our rate of successful engraftment from 74% to 94% (P = 0.043). These results indicate that targeted busulfan dosing optimizes allogeneic engraftment in children.
authors.affiliation: University of California at San Francisco, Department of Clinical Pharmacy, San Francisco, CA 94143-0622, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Bolinger
authors.forename: A B
authors.initials: AB
authors.lastname: Zangwill
authors.forename: J T
authors.initials: JT
authors.lastname: Slattery
authors.forename: L J
authors.initials: LJ
authors.lastname: Risler
authors.forename: D H
authors.initials: DH
authors.lastname: Sultan
authors.forename: D V
authors.initials: DV
authors.lastname: Glidden
authors.forename: D
authors.initials: D
authors.lastname: Norstad
authors.forename: M J
authors.initials: MJ
authors.lastname: Cowan
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D016026:Bone Marrow Transplantation / Q000379:methods* / Q000706:statistics & numerical data; D002066:Busulfan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004334:Drug Administration Schedule; D006084:Graft Rejection / Q000175:diagnosis; D006801:Humans; D007223:Infant; D011446:Prospective Studies; D019172:Transplantation Conditioning / Q000379:methods* / Q000706:statistics & numerical data
chemical_list: D002066:Busulfan