Liposomal busulphan: bioavailability and effect on bone marrow in mice

Abstract

High-dose busulphan is an important component of many BMT conditioning regimens. High-dose busulphan therapy is associated with an increased risk of acute toxicity such as CNS toxicity and veno-occlusive disease (VOD). The toxicity was reported to correlate with a high AUC (area under the curve) during therapy. An intravenous form of busulphan would overcome the problems caused by inter-individual variability and bioavailability of busulphan and most probably minimize the problems with dose adjustment during therapy. The liposomal form of busulphan is an attractive alternative for intravenous administration of busulphan. In the present study, we compared the myeloablative effect of liposomal busulphan (LB) with that of the oral administration form and busulphan dissolved in organic solvent (Bus/DMSO) in mice. The pharmacokinetics of LB and Bus/DMSO were described by one compartment model while the oral data were fitted to one compartment model with first order absorption. The bioavailability of LB was 0.86 ± 0.02 compared to that obtained after the oral administration (0.40–0.74). Myelosuppression was determined using the colony-forming unit granulocyte–macrophage assay (CFU-GM) on days 1, 3, 6 and 9 after the conditioning regimen. LB resulted in significant myelosuppression from day 1 to day 9. The decrease in CFU-GM after conditioning regimen with LB was not significantly different from that observed after oral busulphan. Moreover, the administration of liposomes only to the mice did not affect the bone marrow. No side-effects of the liposomal formulation were observed. We suggest that the novel form of busulphan is a promising drug for clinical use.