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Antimicrobial Agents and Chemotherapy, March 2002, p. 828-833, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.828-833.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics, Excretion, and Mass Balance of Liposomal Amphotericin B (AmBisome) and Amphotericin B Deoxycholate in Humans

Ihor Bekersky,1* Robert M. Fielding,2 Dawna E. Dressler,1,{dagger} Jean W. Lee,3 Donald N. Buell,1 and Thomas J. Walsh4

Fujisawa Healthcare, Inc., Deerfield, Illinois,1 Biologistic Services, Boulder, Colorado,2 MDS Pharma Services, Lincoln, Nebraska,3 Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland4

Received 2 March 2001/ Returned for modification 18 August 2001/ Accepted 12 November 2001

The pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) (liposomal AMB) and the conventional formulation, AMB deoxycholate (AMB-DOC), were compared in a phase IV, open-label, parallel study in healthy volunteers. After a single 2-h infusion of 2 mg of liposomal AMB/kg of body weight or 0.6 mg of AMB-DOC/kg, plasma, urine, and feces were collected for 168 h. The concentrations of AMB were determined by liquid chromatography tandem mass spectrometry (plasma, urine, feces) or high-performance liquid chromatography (HPLC) (plasma). Infusion-related side effects similar to those reported in patients, including nausea and back pain, were observed in both groups. Both formulations had triphasic plasma profiles with long terminal half-lives (liposomal AMB, 152 ± 116 h; AMB-DOC, 127 ± 30 h), but plasma concentrations were higher (P < 0.01) after administration of liposomal AMB (maximum concentration of drug in serum [Cmax], 22.9 ± 10 µg/ml) than those of AMB-DOC (Cmax, 1.4 ± 0.2 µg/ml). Liposomal AMB had a central compartment volume close to that of plasma (50 ± 19 ml/kg) and a volume of distribution at steady state (Vss) (774 ± 550 ml/kg) smaller than the Vss of AMB-DOC (1,807 ± 239 ml/kg) (P < 0.01). Total clearances were similar (approximately 10 ml hr-1 kg-1), but renal and fecal clearances of liposomal AMB were 10-fold lower than those of AMB-DOC (P < 0.01). Two-thirds of the AMB-DOC was excreted unchanged in the urine (20.6%) and feces (42.5%) with >90% accounted for in mass balance calculations at 1 week, suggesting that metabolism plays at most a minor role in AMB elimination. In contrast, <10% of the liposomal AMB was excreted unchanged. No metabolites were observed by HPLC or mass spectrometry. In comparison to AMB-DOC, liposomal AMB produced higher plasma exposures and lower volumes of distribution and markedly decreased the excretion of unchanged drug in urine and feces. Thus, liposomal AMB significantly alters the excretion and mass balance of AMB. The ability of liposomes to sequester drugs in circulating liposomes and within deep tissue compartments may account for these differences.

* Corresponding author. Mailing address: Fujisawa Healthcare, Inc., 3 Pkwy. North, Deerfield, IL 60015-2548. Phone: (847) 317-8696. Fax: (847) 317-5983. E-mail: ihor_bekersky{at}fujisawa.com.

{dagger} Present address: DuPont Pharmaceuticals Company, Wilmington, Del.

Antimicrobial Agents and Chemotherapy, March 2002, p. 828-833, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.828-833.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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