Abstract

Background: Busulfan (Bu) given in myeloablative doses is a frequent component of preparative regimens for hematopoietic stem cell transplantation. Variations in the area under the concentration/time curve (AUC) for oral Bu may result in over/under dosing, which may increase the risk of toxicity or reduce efficacy. The availability of an IV formulation of busulfan reduces this by eliminating variability in absorption but inter-patient differences in metabolism remain. A pharmacokinetically guided test dose strategy before the high dose Bu may be used to achieve a specific target AUC.

Purpose: To establish a reliable model to predict a therapeutic dose of IV Bu from a small test dose in order to improve inter-patient variability in AUC.

Methods: Pharmacokinetic (PK) analysis was performed on 35 paired patient samples, comparing a limited sampling test dose to the therapeutic high dose. For the test dose, an AimPlus infusion pump was used to administer 12 mg of IV Bu over a 20-minute infusion on day −6. High dose Bu was given at a dose of 3.2mg/kg daily over 4 hours on days −5 to −2. The test dose PK parameters were compared to the high dose IV Bu PK parameters on day −3. Busulfan concentrations in plasma were determined by UV-HPLC. All concentration-time plasma Bu data were analyzed by non-compartmental analysis using WinNonlin Version 4.1 software (Pharsight Corporation, Mountain View, CA, USA).

Results: The mean (CV%) PK parameters for the 12 mg test dose patients 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 for the 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 to 7354 μM.min. The ratio of the high dose over the test dose required a correction factor “k” of 1.45 to be equivalent to the ratio of the AUC high dose over the AUC test dose.

Conclusion: Dosing based on patient weight results in 2–3 fold variability of AUC. The fact that a correction factor based on the test dose is needed is most likely due to the statistically significantly higher CL of busulfan during the test dose as compared to the high dose CL. This raises questions concerning the proposed linear kinetics of IV busulfan. However using the above correction factor and given a target therapeutic AUC, it is possible to individualize the therapeutic dose for IV busulfan based on this test dose strategy.

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