Busulfan pharmacokinetics following intravenous and oral dosing regimens in children receiving high-dose myeloablative chemotherapy for high-risk neuroblastoma as part of the HR-NBL-1/SIOPEN trial

Abstract Introduction Busulfan is widely used in a neuroblastoma setting, with several studies reporting marked inter-patient variability in busulfan pharmacokinetics and pharmacodynamics. The current study reports on the pharmacokinetics of oral versus intravenous (IV) busulfan in high-risk neuroblastoma patients treated on the European HR-NBL-1/SIOPEN study. Methods Busulfan was administered four times daily for 4 days to children aged 0.7–13.1 years, either orally (1.45–1.55 mg/kg) or by the IV route (0.8–1.2 mg/kg according to body weight strata). Blood samples were obtained prior to administration, 2, 4, and 6 h after the start of administration on dose 1. Busulfan analysis was carried out by gas chromatography–mass spectrometry and data analysed using a NONMEM population pharmacokinetic approach. Results Busulfan plasma concentrations obtained from 38 patients receiving IV busulfan and 25 patients receiving oral busulfan, were fitted simultaneously using a one-compartment pharmacokinetic model. Lower variability in drug exposure was observed following IV administration, with a mean busulfan area under the plasma concentration versus time curve (AUC) of 1146 ± 187 μM.min (range 838–1622), as compared to 953 ± 290 μM.min (range 434–1427) following oral busulfan. A total of 87% of children treated with IV busulfan achieved AUC values within the target of 900–1500 μM.min versus 56% of patients following oral busulfan. Busulfan AUC values were significantly higher in HR-NBL-1/SIOPEN trial patients who experienced hepatic toxicity or veno-occlusive disease (VOD) (1177 ± 189 μM.min versus 913 ± 256 μM.min; p  = 0.0086). Further stratification based on route of administration suggested that the incidence of hepatic toxicity was related to both high busulfan AUC and oral drug administration. Conclusion The reduced pharmacokinetic variability and improved control of busulfan AUC observed following IV administration support its utility within the ongoing HR-NBL-1/SIOPEN trial.