title: Pharmacokinetics of once-daily IV busulfan as part of pretransplantation preparative regimens: a comparison with an every 6-hour dosing schedule.
abstract: In pretransplantation therapy busulfan is typically given every 6 hours. We infused busulfan once daily at 130 mg/m2 for 4 days, performing pharmacokinetic analyses on plasma concentration-time data (n = 60 patients) on days 1, 3, and/or 4. Mean (percent coefficient of variation) maximum concentration, volume of distribution, half-life, and clearance were 3.6 microg/mL (13.8%), 22.6 L/m2 (20.2%), 2.73 hours (27.5%), and 109 mL/min/m2 (26%), respectively. The mean (percent coefficient of variation) and median daily areas under the curve were 4873 (21.8%) and 4871 microM x minute. Intrapatient variability in day-to-day estimated clearance was <20%, without day-to-day drug accumulation. The pharmokinetic parameters were compared with those from 47 patients given intravenous busulfan at approximately 0.8 mg/kg (approximately 32 mg/m2) every 6 hours. We conclude that there is (1) a dose proportionality based on mean and median areas under the curve, (2) unchanged estimated clearance with a 4-fold increase in dose and a 2.5-fold difference in dosing rate, (3) negligible variability in dose-to-dose pharmacokinetics and negligible interdose accumulation with once-daily administration, and (4) no change in pharmokinetic parameter(s) with concomitant use of imidazole antifungals, oral contraceptives, or phenytoin. In summary, intravenous busulfan has highly predictable, linear pharmacokinetics from 32 mg/m2 (approximately 0.8 mg/kg) to 130 mg/m2 (approximately 3.2 mg/kg). Further, once-daily intravenous busulfan dosing is convenient, favoring its more widespread application.
authors.affiliation: Pharmaceutical Development Center, The University of Texas MD Anderson Cancer Center, Houston, Texas 770554, USA. tmadden@mdanderson.org
authors.forename: Timothy
authors.initials: T
authors.lastname: Madden
authors.forename: Marcos
authors.initials: M
authors.lastname: de Lima
authors.forename: Neil
authors.initials: N
authors.lastname: Thapar
authors.forename: John
authors.initials: J
authors.lastname: Nguyen
authors.forename: Soonja
authors.initials: S
authors.lastname: Roberson
authors.forename: Daniel
authors.initials: D
authors.lastname: Couriel
authors.forename: Betty
authors.initials: B
authors.lastname: Pierre
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Shpall
authors.forename: Roy B
authors.initials: RB
authors.lastname: Jones
authors.forename: Richard E
authors.initials: RE
authors.lastname: Champlin
authors.forename: Borje S
authors.initials: BS
authors.lastname: Andersson
mesh_terms: D000208:Acute Disease; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002066:Busulfan / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D007262:Infusions, Intravenous; D007951:Leukemia, Myeloid / Q000628:therapy; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D009190:Myelodysplastic Syndromes / Q000628:therapy; D019172:Transplantation Conditioning / Q000379:methods*
chemical_list: D019653:Myeloablative Agonists; D002066:Busulfan