Pharmacokinetics and safety of a unilamellar liposomal formulation of amphotericin B (AmBisome) in rabbits

A unilamellar liposomal formulation of amphotericin B (LAmB) known as AmBisome was safely administered intravenously to 20 rabbits at 0.5, 1.0, 2.5, 5, or 10 mg/kg of body weight, whereas of 12 rabbits given desoxycholate amphotericin B (DAmB) intravenously at 0.5, 1.0, or 1.5 mg/kg, 2 died of acute cardiac toxicity when DAmB was administered at the highest dose. Single-dose LAmB (1 mg/kg) achieved a maximum concentration in serum (C(max)) of 26 ± 2.4 μg/ml and an area under the curve to infinity (AUC(0-∞) of 60 ± 16 μg · h/ml, while single-dose DAmB (1.0 mg/kg), by comparison, achieved a lower C(max) (4.7 ± 0.2 μg/ml; P = 0.001) and a lower AUC(0-∞) (30.6 ± 2.2 μg · h/ml; P = 0.07). Following administration of a single dose of LAmB (10 mg/kg), a disproportionately higher C(max) (287 ± 14 μg/ml) and AUC(0-∞) (2,223 ± 246 μg · h/ml) occurred, indicating saturable elimination. After chronic dosing (n = 4) with LAmB at 5.0 mg/kg/day for 28 days or DAmB at 1.0 mg/kg/day for 28 days, LAmB achieved daily peak levels of 122.8 ± 5.8 μg/ml and trough levels of 34.9 ± 1.8 μg/ml, while DAmB reached a peak of only 1.76 ± 0.11 μg/ml and a trough of 0.46 ± 0.04 μg/ml (P ≤ 0.001). Significant accumulations of amphotericin B into reticuloendothelial organs were observed, with 239 ± 39 μg/g found in the liver after chronic LAmB dosing (5 mg/kg/day), which was seven times higher than the 33 ± 6 μg/g after DAmB dosing (1 mg/kg/day) (P = 0.002). Accumulation in kidneys, however, remained 14-fold lower (P = 0.04) following LAmB dosing (0.87 ± 0.61 μg/g) than after DAmB dosing (12.7 ± 4.6 μg/g). Nephrotoxicity occurred in only one of four LAmB-treated animals, while it occurred in all four chronically DAmB-treated animals; mild hepatotoxicity with transaminase elevations was seen in one LAmB-treated rabbit. We conclude that LAmB safely achieved higher C(max)s and AUC(0-∞)s and demonstrated saturable, nonlinear elimination from plasma via reticuloendothelial organ uptake. The reduced nephrotoxicity of LAmB correlated with diminished levels of amphotericin B in the kidneys.