Phase I study utilizing an intravenous busulfan test dose to prospectively target and determine the maximum tolerated systemic exposure (MTSE) of a continuous intravenous infusion

Abstract

16502 Background: Busulfan systemic concentration has correlated with toxicity and efficacy. We previously demonstrated that administration of intravenous high-dose busulfan (HD-Bu) as a 90 hour continuous infusion (CIV) has efficacy, safety, and mean daily area under the concentration curves (AUC) comparable to intermittent dosing regimens and that it is possible to use a test dose of busulfan to predict the systemic exposure with less than 10% variability. The objective of this study is to identify the MTSE of CIV HD-Bu utilizing a test dose for AUC targeting. Methods: Prior to HD-Bu, patients received a single test dose of Bu (0.8 mg/kg) by two hour infusion with blood concentrations obtained at 0, 2.5, 4, 5, and 6 hours. Serum concentrations were analyzed using GC-MS. Non-compartmental PK analysis was used to determine clearance using WIN-NONLIN software. The systemic clearance (dose/AUC) of the test dose was used to predict the 90 hour CIV dose of Bu needed to achieve the desired AUC. On days -7 to -3, the treatment dose was administered and blood samples were collected at 0, 12, 16, 18, 48, 60, 72, and 89.5 hours to verify that the desired AUC was reached. Dose adjustments were made after 18 hours if necessary. A blood sample was obtained for evaluation of polymorphisms in genes associated with busulfan metabolism and transport. Results: Five patients (4 MUD, 1 matched-sibling donor) were enrolled at the 24 hour Bu target AUC of 4800 uM*min ± 15%. One patient was not able to be evaluated due to errors in PK acquisition. 3 of the 4 patients required CIV doses different than that based on weight alone (i.e. 12.8 mg/kg). All 4 patients had AUCs within the desired range (mean 24 hour busulfan AUC of 4708 uM*min) with a mean bias and precision of −1.9% and 8.7%, respectively. No adjustments were required after 18 hours. No grade 3 or greater chemotherapy related toxicity has been identified. Conclusions: The systemic clearance determined by a busulfan test dose may be used to prospectively target the desired AUC of a 90 hour CIV. Enrollment on this Phase I study will continue beyond the first dose level which is at the upper limit of the normal range (4800 uM*min). No significant financial relationships to disclose.