title: Highly variable pharmacokinetics of once-daily intravenous busulfan when combined with fludarabine in pediatric patients: phase I clinical study for determination of optimal once-daily busulfan dose using pharmacokinetic modeling.
abstract: Busulfan has a narrow therapeutic range, and in children, pharmacokinetic variability has been found to be high even after the use of intravenous (i.v.) busulfan. Recently, a reduced toxicity myeloablative regimen showed promising results, but the data of busulfan pharmacokinetics in hematopoietic stem cell transplantation (HSCT) using a targeted busulfan/fludarabine regimen in children has not yet been reported. We performed therapeutic drug monitoring (TDM) after once-daily i.v. busulfan combined with fludarabine and analyzed the outcomes. Busulfan (i.v.) was administered once daily for 4 consecutive days. The daily target area under the curve (AUC) was 18,125-20,000 μg*h/L/day (4415-4872 μmol*min/L/day), which was reduced to 18,000-19,000 μg*h/L/day (4384-4628 μmol*min/L/day) after a high incidence of toxicity was observed. A total of 24 patients were enrolled. After infusion of busulfan on the first day, patients showed AUC that ranged from 12,079 to 31,660 μg*h/L (2942 to 7712 μmol*min/L) (median 16,824 μg*h/L, percent coefficient of variation (%CV) = 26.5%), with clearance of 1.74-6.94 mL/min/kg (median 4.03 mL/min/kg). We performed daily TDM in 20 patients, and during the daily TDM, the actual AUC ranged from 73% to 146% of the target AUC, showing high intraindividual variability. The %CV of busulfan clearance of each individual ranged from 7.7% to 38.7%. The total dose of busulfan administered for 4 days ranged from 287.3 mg/m(2) to 689.3 mg/m(2). Graft failure occurred in 3 patients with total AUC less than 74,000 μg*h/L (18,026 μmol*min/L), and 2 patients with relatively high total AUC experienced veno-occlusive disease. Busulfan pharmacokinetics showed high inter- and intraindividual variability in HSCT using a targeted busulfan/fludarabine regimen, which indicates the need for intensive monitoring and dose adjustment to improve the outcome of HSCT. Currently, we are performing a newly designed phase II study to decrease regimen-related toxicities and reduce graft failure by setting an optimal target AUC based on this study.
authors.affiliation: Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Hyoung Jin
authors.initials: HJ
authors.lastname: Kang
authors.forename: Seung Hwan
authors.initials: SH
authors.lastname: Lee
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
authors.forename: Nam Hee
authors.initials: NH
authors.lastname: Kim
authors.forename: Yen Ju
authors.initials: YJ
authors.lastname: Yuk
authors.forename: Mi Kyoung
authors.initials: MK
authors.lastname: Jang
authors.forename: Eun Jong
authors.initials: EJ
authors.lastname: Han
authors.forename: Hyery
authors.initials: H
authors.lastname: Kim
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Song
authors.forename: Kyung Duk
authors.initials: KD
authors.lastname: Park
authors.forename: Hee Young
authors.initials: HY
authors.lastname: Shin
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Hyo Seop
authors.initials: HS
authors.lastname: Ahn
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016026:Bone Marrow Transplantation; D002066:Busulfan / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000628:therapy*; D008297:Male; D015233:Models, Statistical; D036102:Peripheral Blood Stem Cell Transplantation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000628:therapy*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine