Pharmacokinetics of once daily IV busulfan: Implications of fixed-infusion rate dosing

931 Busulfan (Bu) given in myeloablative doses is a frequent component of cytotoxic preparative regimens for hematopoietic stem cell transplantation. Previously we have shown that it is feasible to individualize the dose of Bu based on a pharmacokinetically guided test dose strategy prior to administration of high dose Bu. We also found that exposure to Bu as indicated by area under the concentration/time curve (AUC) above 6000 µM.min is associated with poorer clinical outcome. Intravenous (IV) chemotherapy agents typically are infused over a set time and based on the patient’s weight (W) or body surface area (BSA). Due to variability in W and BSA among different patients the rate of infusion can vary over two-fold, and this variability often influences drug kinetics. Objectives: To optimize IV Bu in a manner that would allow predictable kinetics for individualized dose modification in order to avoid Bu exposure above an AUC of 6000 µM.min associated with toxicities. Methods: Pharmacokinetic (PK) analysis was performed on 121 patients given 3.2 mg/kg IV Bu over a 3 hr infusion, and 54 patients dosed at 3.2 mg/kg IV Bu at a fixed infusion rate of 80 mg/hr. Bu concentrations in plasma were determined by UV-HPLC. All PK data were analyzed by non-compartmental and compartmental analysis using WinNonlin Version 5.0.1 software (Pharsight Corporation, Mountain View, CA, USA). Results: The mean (±SD) rate of infusion for the 3 hr dosing was 78.3 ± 13 mg/hr with an observed range of 50 mg/hr to 119 mg/hr. The observed range of AUC for the 3 hr IV dosing was 2184 µM.min to 7794 µM.min whereas this range for the 80 mg/hr dosing was 2557 µM.min to 5296 µM.min. There was less variability observed in the kinetics of IV Bu with the fixed-infusion rate dosing. The mean (% coefficient of variance) AUC for the 80 mg/hr dosing was 3872 (17%) µM.min and the mean (% CV) for the 3 hr dosing was 4707 (24%) µM.min. The distributions for the two populations were compared by the Kolmogorov-Smirnov test (KS-test). The maximum difference between the cumulative distributions (D) was 0.42 with a P-value of 3000 µM.min. Conclusions: IV busulfan given at a fixed infusion rate has predictable and more consistent kinetics as compared to when Bu is given over a fixed time period. This allows for more reliable and accurate dose adjustment of this drug where it was not possible to achieve with fixed-time dosing. These results justify further research and debate about whether other IV chemotherapy agents should be infused with a fixed-infusion rate, and whether fixed-infusion rate dosing protocols should be used during phase I dose escalating pharmacokinetic trials.

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