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Antimicrobial Agents and Chemotherapy, January 2008, p. 259-268, Vol. 52, No. 1
0066-4804/08/$08.00+0     doi:10.1128/AAC.00870-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Comparison of the Physicochemical, Antifungal, and Toxic Properties of Two Liposomal Amphotericin B Products

Department of Biological Sciences, California State Polytechnic University, Pomona, California 91768,¹ Gilead Sciences, Inc., 650 Cliffside Drive, San Dimas, California 91773,² Pathology Associates Division, Charles River Laboratories, Inc., Davis, California 95616,³ Foundation for the Fight Against Leukemia, Buenos Aires 1114, Argentina,⁴ RichPro Associates, 2095 Lavender Hill Court, Lincoln, California 95648⁵

Received 3 July 2007/ Returned for modification 24 August 2007/ Accepted 23 October 2007

Small unilamellar amphotericin B liposomes can reduce the toxicity of amphotericin B. In this study, we compared the physical, antifungal, pharmocokinetic, and toxic properties of two liposomal amphotericin B products, AmBisome and Anfogen, that have the same chemical composition but are manufactured differently. In vitro tests included determinations of the MICs and the concentrations causing the release of 50% of the intracellular potassium from red blood cells (K₅₀ values) to assess toxicity. The 50% lethal dose (LD₅₀) was evaluated by using uninfected C57BL/6 mice and single intravenous (i.v.) doses of 1 to 100 mg/kg of body weight. Multiple i.v. dosing over 18 days was performed with 0.5, 1.0, or 5.0 mg of Anfogen/kg or 1.0, 5.0, or 25 mg of AmBisome/kg to evaluate chronic toxicity. DBA/2 mice were infected intranasally with 2.5 x 10⁶ Aspergillus fumigatus conidia, treated for 3 or 4 days with 3.0, 5.0, or 7.5 mg of Anfogen/kg or 3, 5, 7.5, or 15 mg of AmBisome/kg, and evaluated to assess the toxicity of the drugs to the kidneys (by measurement of blood urea nitrogen and creatinine levels and histopathology) and the drug efficacy. The median particle size was 77.8 nm for AmBisome and 111.5 nm for Anfogen. In vitro K₅₀ values were significantly lower for Anfogen (0.9 µg/ml) than for AmBisome (20 µg/ml), and the LD₅₀ of AmBisome was >100 mg/kg, versus 10 mg of Anfogen/kg. There was significant renal tubular necrosis in uninfected and infected mice given Anfogen but no tubular necrosis in AmBisome-treated mice. AmBisome at 7.5 or 15 mg/kg was also more efficacious than 7.5 mg of Anfogen/kg for the treatment of pulmonary aspergillosis, based on survival and weight loss data and numbers of CFU per gram of lung. In conclusion, the efficacy and toxicity of these two liposomal amphotericin B products were significantly different, and thus, the products were not comparable.

Published ahead of print on 29 October 2007.