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Antimicrobial Agents and Chemotherapy, February 1998, p. 263-268, Vol. 42, No. 2
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Toxicological Profile and Pharmacokinetics of a Unilamellar Liposomal Vesicle Formulation of Amphotericin B in Rats

Garry W. Boswell,1,* Ihor Bekersky,1 Donald Buell,1 Richard Hiles,1,dagger and Thomas J. Walsh2

Fujisawa USA, Inc., Deerfield, Illinois,1 and National Cancer Institute, Bethesda, Maryland2

Received 9 May 1997/Returned for modification 10 October 1997/Accepted 15 November 1997

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 µg/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.

* Corresponding author. Mailing address: Fujisawa USA, Inc., 3 Parkway North, Deerfield, IL 60015-2548. Phone: (847) 317-1094. Fax: (847) 317-7295. E-mail: garry_boswell{at}FujisawaUSA.com.

dagger Present address: Chrysalis Inc., Waverly, Pa.

Antimicrobial Agents and Chemotherapy, February 1998, p. 263-268, Vol. 42, No. 2
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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