Tissue distribution and antifungal effect of liposomal itraconazole in experimental cryptococcosis and pulmonary aspergillosis

Abstract

We studied the tissue distribution and in vivo antifungal effect of itraconazole, incorporated into pure dipalmitoylphosphatidylcholine (DPPC) multilamellar liposomes and administered intravenously. Eighty percent of the itraconazole was associated with DPPC. Drug levels in lung, brain, and liver, obtained after intravenous administration of tritiated itraconazole, were higher when the drug was administered intravenously as liposomal than when it was dissolved in cyclodextrin. Administration of the liposomal formulation also led to higher and sustained levels of intact itraconazole in serum. Efficacy was assessed in DBA/2 mice infected intravenously with 3 x 10(6) Cryptococcus neoformans, an inoculum responsible for early fatal pneumonia, or 3 x 10(5) C. neoformans, leading to delayed meningitis. In pneumonia, 20 mg/kg of liposomal itraconazole was more effective on survival than the same dose given intravenously in cyclodextrin or twice the dose administered orally dissolved in polyethylene glycol 200. In meningitis, liposomal itraconazole was also more efficient than the drug dissolved in cyclodextrin. These results were confirmed by colony counts in the brain and lung of infected mice. In immunosuppressed OF1 mice infected after inhalation of Aspergillus fumigatus spores, liposomal itraconazole (20 mg/kg x 3) was the only effective treatment. We conclude that intravenous liposomal delivery of itraconazole enhances both concentrations in infected tissues and the in vivo efficacy of the drug. Such passive targeting of antifungal agents other than amphotericin B might be helpful in the treatment of severe systemic mycoses, especially in the case of lung or brain involvement.