Safety, efficacy, and pharmacokinetics of intravenous busulfan in children undergoing allogeneic hematopoietic stem cell transplantation.
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.
Wall
Donna A
DA
Cardinal Glennon Children's Hospital/Saint Louis University, St. Louis, Missouri, USA. donna.wall@cancercare.mb.ca
Chan
Ka Wah
KW
Nieder
Michael L
ML
Hayashi
Robert J
RJ
Yeager
Andrew M
AM
Kadota
Richard
R
Przepiorka
Donna
D
Mezzi
Khaled
K
Kletzel
Morris
M
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
D019653:Myeloablative Agonists; D002066:Busulfan