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 mug/ml and an area under the curve to infinity (AUC0-infinity) of 60 +/- 16 mug . h/ml, while single-dose DAmB (1.0 mg/kg), by comparison, achieved a lower C(max) (4.7 +/- 0.2 mug/ml; P = 0.001) and a lower AUC0-infinity (30.6 +/- 2.2 mug . h/ml; P = 0.07). Following administration of a single dose of LAmB (10 mg/kg), a disproportionately higher C(max) (287 +/- 14 mug/ml) and AUC0-infinity (2,223 +/- 246 mug . 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 mug/ml and trough levels of 34.9 +/- 1.8 mug/ml, while DAmB reached a peak of only 1.76 +/- 0.11 mug/ml and a trough of 0.46 +/- 0.04 mug/ml (P less-than-or-equal-to 0.001). Significant accumulations of amphotericin B into reticuloendothelial organs were observed, with 239 +/- 39 mug/g found in the liver after chronic LAmB dosing (5 mg/kg/day), which was seven times higher than the 33 +/- 6 mug/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 mug/g) than after DAmB dosing (12.7 +/- 4.6 mug/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-infinity)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.