Busulfan was available primarily as an oral formulation until recently. The oral drug has variable bioavailability that has been linked to erratic gastrointestinal absorption from patient to patient. In a phase I trial, Andersson et al evaluated an IV Bu formulation using dimethylacetamide and PEG400 as the solvent. This is the formulation currently marketed in the USA (Busulfex ESP Pharma). Fifteen patients with advanced hematologic malignancies were treated with BU every 6 hours for a total of 16 doses followed by cyclophosphamide (CY) 60mg/kg for 2 doses and hematopoietic cell transplant. The first BU dose given was by IV. The starting IV dose was 0.08mg/kg which was then escalated to 0.2, 0.4, and finally to 0.8mg/kg in cohorts of 3 patients each. Six hours after the start of the IV BU infusion, the patients began to receive oral BU 1mg/kg every 6 hours for 15 doses. Pharmacokinetic profiles were obtained to determine an equivalent exposure of IV BU to the oral BU dose of 1mg/kg. It was noted that the toxicity profile and rates of engraftment were similar to that of the oral drug (i.e., no additional toxicities were found attributable to the solvents). An IV dose of 0.8mg/kg gave an equivalent AUC (but with less variability) as the oral dose of 1mg/kg with a mean AUC of 1189 micrometer (uM)-min (range 964-1547uM-min; 24h DIE 4756uM-min [range 3856-6188uM-min]). Thus, 0.8mg/kg was chosen by the investigators as the dose to proceed to phase II testing. A subsequent phase II multicenter trial in 61 patients with a variety of hematologic malignancies using 0.8mg/kg every 6 hours x 16 doses of IV BU and 120mg/kg CY prior to hematopoietic stem cell transplant. Pharmacokinetic analyses were also done. Once again, it was shown that the toxicity and outcome data was similar to that published for the oral BU. There were no patients with seizures. Lung toxicities occurred in two patients, one with diffuse alveolar hemorrhage (DAH) and one with interstitial pneumonitis (IP); the latter patient had a history of lung irradiation. Grade 1-2 nausea and emesis occurred in 43% and grade 3 in 7%. Mucositis was grade 2 in 44%, Grade 3 in 26% and lasted a median of 6 days. There were five (8%) cases of veno-occlusive disease (VOD), which was fatal in two (3%). Treatment related mortality at 100 days was 9.8%. The AUC was <1500 uM-min (24h DIE <6000uM-min) in 55%; 86% of patients maintained an AUC between 800 and 1500uM-min (24h DIE 3200-6000uM-min). The AUC at dose 1 and dose 9 were similar indicating a consistent dose-to-dose behavior. The authors concluded that IV BU in this setting was well tolerated and demonstrated excellent antitumor efficacy, likely resulting from predictable pharmacokinetics. Based on these and other studies, IV administration has become the preferred route for BU when given in the high dose transplant setting. Fernandez, et al. evaluated the use of IV Bu (Busulfex® ESP Pharma) in either a once daily or twice daily dosing schedule when given as a part of BUCY regimen (BU: 3.2 mg/kg and CY 120mg/kg) prior to transplant. In both dosing schedules, there was little variability in the dose-to-dose levels and the pharmacokinetics of the first dose could predict the data on subsequent doses. In the twice-daily group, AUC 3390uM-min (2400- 4678uM-min; 24h DIE 6780uM-min [4800-9356uM-min]) and the once daily group the AUC 5561uM-min (4412 - 7368uM-min). The pharmacokinetic profiles (AUC, CL, Cmax and t 1/2) were similar from dose to dose. In the twelve patients studied, the following grade 3 toxicities were reported: mucositis, anorexia, infection, epistaxis and hyperglycemia. Two patients died: one from sepsis from presumed fungal infection and one sudden cardiac death. One patient developed mild, reversible VOD. Daily dosing of IV Bu results in similar outcomes and toxicity profile compared to oral dosing and ease in delivering a targeted exposure of BU. The importance of being able to target BU exposure has been illustrated in the above discussion of reports correlating BU pharmacokinetic parameters with its toxicity and efficacy. Thus, by utilizing a once daily IV dose, targeted to prespecified levels, BU therapy can be optimized to limit toxicity and maximize efficacy.