Individualized Once-Daily Dosing of Intravenous Busulfan: A Pharmacokinetic Study in Patients Undergoing Conditioning for Allogeneic Stem Cell Transplantation.
Journal - ASH Annual Meeting Abstracts
Background: Busulfan (Bu) given in myeloablative doses is afrequent component of preparative regimens for hematopoieticstem cell transplantation. Variations in the area under theconcentration/time curve (AUC) for oral Bu may result in over/underdosing, which may increase the risk of toxicity or reduce efficacy.The availability of an IV formulation of busulfan reduces thisby eliminating variability in absorption but inter-patient differencesin metabolism remain. A pharmacokinetically guided test dosestrategy before the high dose Bu may be used to achieve a specifictarget AUC.
Purpose: To establish a reliable model to predict a therapeuticdose of IV Bu from a small test dose in order to improve inter-patientvariability in AUC.
Methods: Pharmacokinetic (PK) analysis was performed on 35 pairedpatient samples, comparing a limited sampling test dose to thetherapeutic high dose. For the test dose, an AimPlus infusionpump was used to administer 12 mg of IV Bu over a 20-minuteinfusion on day –6. High dose Bu was given at a dose of3.2mg/kg daily over 4 hours on days –5 to –2. Thetest dose PK parameters were compared to the high dose IV BuPK parameters on day –3. Busulfan concentrations in plasmawere determined by UV-HPLC. All concentration-time plasma Budata were analyzed by non-compartmental analysis using WinNonlinVersion 4.1 software (Pharsight Corporation, Mountain View,CA, USA).
Results: The mean (CV%) PK parameters for the 12 mg test dosepatients were as follows: Cmax, 0.36 ug/mL (30.4%); clearance(CL), 16.3 L/hr (21.4%); volume of distribution Vd, 57.4 L (26.1%);elimination half-life, 2.4 hr (16.1%); and AUC, 199 µM.min(23.6%). The mean (CV%) Cmax, CL, Vd, half-life, and AUC forthe once daily high dose were 3.95 ug/mL (22%), 11.7 L/hr (25.4%),46.3 L (25.3%), 2.8 hr (15.6%), and 5190 µM.min (22.7%)respectively. The range of AUC for the high dose was 2832 to7354 µM.min. The ratio of the high dose over the testdose required a correction factor "k" of 1.45 to be equivalentto the ratio of the AUC high dose over the AUC test dose.
Conclusion: Dosing based on patient weight results in 2–3fold variability of AUC. The fact that a correction factor basedon the test dose is needed is most likely due to the statisticallysignificantly higher CL of busulfan during the test dose ascompared to the high dose CL. This raises questions concerningthe proposed linear kinetics of IV busulfan. However using theabove correction factor and given a target therapeutic AUC,it is possible to individualize the therapeutic dose for IVbusulfan based on this test dose strategy.