TY - JOUR
T1 - Pharmacokinetics of Once-Daily IV Busulfan as Part of Pretransplantation Preparative Regimens
T2 - A Comparison with an Every 6-Hour Dosing Schedule
AU - Madden, Timothy
AU - de Lima, Marcos
AU - Thapar, Neil
AU - Nguyen, John
AU - Roberson, Soonja
AU - Couriel, Daniel
AU - Pierre, Betty
AU - Shpall, Elizabeth J.
AU - Jones, Roy B.
AU - Champlin, Richard E.
AU - Andersson, Borje S.
N1 - Funding Information:
This study was supported in part by National Institutes of Health grants 2PO1 CA55164 and 2P30CA16672-26 and by a grant from the Steven and Lavinia Boyd Fund for Leukemia Research.
PY - 2007/1
Y1 - 2007/1
N2 - 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 μg/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 μM × 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 ∼0.8 mg/kg (∼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 (∼0.8 mg/kg) to 130 mg/m2 (∼3.2 mg/kg). Further, once-daily intravenous busulfan dosing is convenient, favoring its more widespread application.
AB - 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 μg/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 μM × 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 ∼0.8 mg/kg (∼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 (∼0.8 mg/kg) to 130 mg/m2 (∼3.2 mg/kg). Further, once-daily intravenous busulfan dosing is convenient, favoring its more widespread application.
KW - Acute myeloid leukemia
KW - Hemopoietic stem cell transplantation
KW - Intravenous busulfan
KW - Myelodysplastic syndrome
KW - Once-daily busulfan administration
KW - Pharmacokinetics
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U2 - 10.1016/j.bbmt.2006.08.037
DO - 10.1016/j.bbmt.2006.08.037
M3 - Article
C2 - 17222753
AN - SCOPUS:33845984552
SN - 1083-8791
VL - 13
SP - 56
EP - 64
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 1
ER -