Toxicological profile and pharmacokinetics of a unilamellar liposomal vesicle formulation of amphotericin B in rats.
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 microg/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.
Boswell
G W
GW
Fujisawa USA, Inc., Deerfield, Illinois 60015-2548, USA. garry_boswell@FujisawaUSA.com
Bekersky
I
I
Buell
D
D
Hiles
R
R
Walsh
T J
TJ
D000666:Amphotericin B / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004337:Drug Carriers; D005260:Female; D008081:Liposomes; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000935:Antifungal Agents; D004337:Drug Carriers; D008081:Liposomes; D000666:Amphotericin B