Liposomal busulphan: bioavailability and effect on bone marrow in mice

Area of Science:

• Pharmacology
• Hematology
• Drug Delivery Systems

Background:

• High-dose busulphan is crucial for bone marrow transplantation (BMT) conditioning but carries risks of toxicity, including CNS toxicity and veno-occlusive disease (VOD).
• Toxicity is linked to high area under the curve (AUC) of busulphan, necessitating precise dose adjustments due to inter-individual variability and poor oral bioavailability.
• Intravenous administration could mitigate these issues, with liposomal busulphan (LB) emerging as a potential alternative for improved delivery.

Purpose of the Study:

• To compare the myeloablative efficacy of liposomal busulphan (LB) against oral busulphan and busulphan in organic solvent (Bus/DMSO) in a murine model.
• To evaluate the pharmacokinetics and bioavailability of LB.
• To assess the safety and side-effects of the liposomal formulation.

Main Methods:

• Pharmacokinetic analysis using one-compartment models for LB and Bus/DMSO, and a one-compartment model with first-order absorption for oral busulphan.
• Assessment of myelosuppression via colony-forming unit granulocyte-macrophage (CFU-GM) assays on days 1, 3, 6, and 9 post-conditioning.
• Evaluation of bone marrow effects and side-effects from liposome administration alone.

Main Results:

• Liposomal busulphan (LB) demonstrated significantly higher bioavailability (0.86±0.02) compared to oral busulphan (0.40-0.74).
• LB induced significant myelosuppression from day 1 to day 9, comparable to oral busulphan.
• Administration of liposomes alone did not impact bone marrow, and no adverse effects were observed with the LB formulation.

Conclusions:

• Liposomal busulphan (LB) presents a promising alternative for intravenous administration, offering improved bioavailability and effective myelosuppression.
• The LB formulation appears safe and well-tolerated in mice, without adverse effects on bone marrow.
• LB holds potential for clinical application in BMT conditioning regimens, potentially reducing toxicity associated with current busulphan therapies.