90 hour continuous intravenous busulfan infusion: PK and test dose predictability in allogenic bone marrow transplantation patients

Abstract

6652 Background: Precise and predictable dosing of busulfan is important in pre-transplant conditioning regimens because the AUC of high dose busulfan (HD-Bu) has been correlated with toxicity, engraftment and relapse. Use of a continuous infusion, rather than traditional bolus dosing, would theoretically produce a target busulfan concentration within the desired range throughout the four-day interval. This consistency in concentration may be associated with superior safety and efficacy. The objective of this study is to evaluate the ability of a test dose to predict steady state systemic exposure of a continuous 90 hour infusion of HD-Bu. Methods: The day prior to HD-Bu, seven patients received a single test dose of intravenous busulfan (0.8 mg/kg) by two hour infusion with blood concentrations obtained at 0, 2, 4, 6, and 8 hours. Busulfan 12 mg/kg continuous infusion over 90 hours was then administered and blood samples were collected at 0, 6, 12, 18, 24, 36, 48, 60, 72, 84, 90, 92 and 96 hours. Serum concentrations were analyzed using GC-MS and noncompartmental pharmacokinetic analysis to determine clearance was performed using WIN-NONLIN. The systemic clearance (dose/AUC) of the test dose was compared with the continuous infusion. Results: Mean (range) clearance for the test and continuous infusion was 18238 mL/hr (10444 33884) and 18128 mL/hr (10004 32491), respectively. Bias and precision for the test dose compared with the continuous infusion were 0.6% and 9%, respectively. Conclusions: These data suggest the systemic clearance determined from a busulfan test dose may be used to target therapeutic AUC of a 90 hour continuous infusion. No significant financial relationships to disclose.