Toxicological profile and pharmacokinetics of a unilamellar liposomal vesicle formulation of amphotericin B in rats
Boswell, G.W.; Bekersky, I.; Buell, D.; Hiles, R.; Walsh, T.J.
Antimicrobial Agents and ChemoTherapy 42(2): 263-268
1998
ISSN/ISBN: 0066-4804 PMID: 9527770 Document Number: 495885
AmBisome (ABLP) is a unilamellar liposomal preparation of amphotericin B that has demonstrated an improved safety profile compared to conventional amphotericin B. Single- and multiple-dose pharmacokinetics were determined by using noncompartmental methods for rats administered ABLP at 1, 3, 9, and 20 mg/kg/day. The toxicological profile was evaluated following 30 consecutive days of intravenous ABLP administration. Mean plasma amphotericin B concentrations reached 500 and 380 mug/ml (males and females, respectively) following 30 days of ABLP administration at 20 mg/kg. The overall apparent half-life was 11.2 +- 4.5 h (males) or 8.7 +- 2.2 h (females), and the overall clearance (CL) was 9.4 +- 5.5 ml/h/kg (males) or 10.2 +- 4.1 ml/h/kg (females). ABLP appears to undergo saturable disposition, resulting in a non-dose-proportional amphotericin B area under the curve and a lower CL at higher doses. Histopathological examination revealed dose-related transitional-cell hyperplasia in the transitional epithelium of the urinary tract (kidney, ureters, and urinary bladder) and moderate hepatocellular necrosis at the 20-mg/kg/day dose. Administration of ABLP in doses of up to 20 mg/kg/day resulted in 100-fold higher plasma amphotericin B concentrations, with significantly lower toxicity than that reported with conventional amphotericin B therapy.