title: Safety, efficacy, and pharmacokinetics of intravenous busulfan in children undergoing allogeneic hematopoietic stem cell transplantation.
abstract: OBJECTIVE
  To determine the safety, efficacy, and PK profile of intravenous busulfan (Bu) in the context of a Bu and cyclophosphamide (IVBuCy) preparative regimen in children undergoing allogeneic hematopoietic stem cell transplantation (HSCT).
  
  
  METHODS
  Twenty-four children were enrolled in an open-label, multicenter trial of IVBuCy as the preparative regimen for HLA-matched sibling allogeneic HSCT. IVBu was administered q6 hr for 16 doses with a targeted area under the curve (AUC) of 900-1,350 microMol-min. The initial dose was 0.8 mg/kg for children >4 years of age and 1 mg/kg for those <4 years of age. PK of the first dose IVBu was determined to calculate a single dosage adjustment, and with the 9th and 13th doses to confirm steady-state PK.
  
  
  RESULTS
  The targeted AUC was achieved with the first dose in 17/24 (71%) of the children using the age-adjusted dosing approach. Dosing was increased in five patients, and reduced in two patients to achieve target values. After dose adjustment based on PK, 91% of the children had an AUC within the target range at steady state (AUCss). Median final dosing and clearance (CL) of IVBu were 1.1 mg/kg and 4.1 ml/min/kg in patients < or =4 years, and 0.9 mg/kg and 2.9 ml/min/kg in patients >4 years. All children were engrafted with documented donor chimerism. No late rejections or graft failures occurred. Four patients had veno-occlusive disease, three of which resolved within 2 weeks of onset. Two children died from transplant-related causes unrelated to Bu.
  
  
  CONCLUSIONS
  IVBu is a safe and effective and offers the benefit of predictable and consistent systemic exposure.
authors.affiliation: Cardinal Glennon Children's Hospital/Saint Louis University, St. Louis, Missouri, USA. donna.wall@cancercare.mb.ca
authors.forename: Donna A
authors.initials: DA
authors.lastname: Wall
authors.forename: Ka Wah
authors.initials: KW
authors.lastname: Chan
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nieder
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hayashi
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Yeager
authors.forename: Richard
authors.initials: R
authors.lastname: Kadota
authors.forename: Donna
authors.initials: D
authors.lastname: Przepiorka
authors.forename: Khaled
authors.initials: K
authors.lastname: Mezzi
authors.forename: Morris
authors.initials: M
authors.lastname: Kletzel
mesh_terms: D000293:Adolescent; D019540:Area Under Curve; D002066:Busulfan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D019653:Myeloablative Agonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D011446:Prospective Studies; D016019:Survival Analysis; D014184:Transplantation, Homologous
chemical_list: D019653:Myeloablative Agonists; D002066:Busulfan