Safety, Efficacy, and Pharmacokinetics of Intravenous Busulfan in Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Purpose. 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 mu Mol-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 closes 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 close adjustment based on PK, 91% of the children had an AUC within the target range at steady state (AUCss). Median final closing and clearance (CL) of IVBu were 1.1 mg/kg and 4.1 ml/min/kg in patients <= 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. Conclusion. IVBu is a safe and effective and offers the benefit of predictable and consistent systemic exposure. Pediatr Blood Cancer 2010;54:291-298. (C) 2009 Wiley-Liss, Inc.