Comparative pharmacokinetics and safety of a novel lyophilized amphotericin B lecithin-based oil-water microemulsion and amphotericin B deoxycholate in animal models

Amphotericin B (AmB) has been a most effective systemic antifungal agent, but its use is circumscribed by the dose-limiting toxicity of the conventional micellar dispersion formulation Fungizone (D-AmB). To lower AmB-associated toxicity, AmB may be integrated into oil-in-water lecithin-based microemulsions. The present study compares the pharmacokinetic characteristics of D-AmB with the alternative formulation of AmB in microemulsion (M-AmB), which has proved effective in a murine candidiasis model. Both formulations were given by intravenous bolus: D-AmB 1 mg/kg, and M-AmB 0.5, 1 or 2 mg/kg. The pharmacokinetics of D-AmB and M-AmB have several differences, specifically with regard to the respective C-max and AUC(0-infinity) values. Elimination of AmB from serum was biphasic for both M-AmB and D-AmB. Single-dose D-AmB (1 mg/kg) achieved a C-max of 3.89 +/- 0.48 mg/L and an AUC(0-infinity) of 32.28 +/- 7.31 mg.h/L, whereas single-dose M-AmB (1 mg/kg) by comparison achieved a lower C-max (2.92 +/- 0.54 mg/L) and a lower AUC(0-infinity) (21.89 +/- 5.17 mg.h/L). To evaluate the safety of M-AmB, a multiple-dose toxicity study was performed in groups of 10 mice, each receiving D-AmB 1 mg/kg, or M-AmB 1, 1.5, 2 or 3 mg/kg. The findings suggest that, in comparison with D-AmB, M-AmB produces no histologically demonstrable renal lesions, or changes in clinical chemistry.