Pharmacokinetics and Tolerability of Intravenous Busulfan in Hematopoietic Stem Cell Transplantation.

Intravenous (IV) busulfan has been developed to overcome variable absorption of oral busulfan and tested in several trials. We tested its pharmacological properties and tolerability in 16 Korean SCT patients. IV busulfan was administered at 0.8 mg/kg every 6 hours for a total of 16 doses (days -7 to -4), which was followed by cyclophosphamide administration at 60 mg/kg every 24 hours for 2 days (days -3 and -2). The median AUC_inf values (at the 1^st dose) and AUC_ss (at the steady state) were 1060.4 mM·min (range: 511.1– 1812.7) and 1092.5 mM·min (range: 539.7 – 1560.8), respectively. All patients had an AUC_inf of < 1500 mM·min at the 1^st dose, and 13 of the 16 (81.3 %) maintained AUC_ss levels between 800 and 1500mM·min. Overall, pharmacokinetics of IV busulfan in our SCT patients appeared comparable to those observed in other study. Thirteen of 16 patients achieved successful engraftments but 4 patients (25%) developed hepatic VOD (2 of which were fatal). Although there was no apparent correlation between AUC and hepatic VOD development, 3 out of 4 patients with VOD had advanced disease at the time of SCT. Notably, patients who had uncontrolled diseases (CML blast crisis, ALL 2^nd relapse) succumbed to VOD and those who survived VOD had less advanced disease (CML CP, ALL in 2^nd CR) at the time of SCT. In conclusion, pharmacokinetics of IV busulfan in our SCT patients appeared comparable to those observed in other studies, however, hepatic VOD was still a major morbidity, especially in patients with advanced disease, warranting consideration of other parameters in addition to pharmacokinetic monitoring of IV busulfan to decrease VOD in high risk patient populations.