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Antimicrobial Agents and Chemotherapy, September 1998, p. 2391-2398, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Safety, Tolerance, and Pharmacokinetics of a Small Unilamellar Liposomal Formulation of Amphotericin B (AmBisome) in Neutropenic Patients

Thomas J. Walsh,1,* Vijay Yeldandi,2 Maureen McEvoy,1 Corina Gonzalez,1 Stephen Chanock,1 Alison Freifeld,1 Nita I. Seibel,3 Patricia O. Whitcomb,4 Paul Jarosinski,5 Garry Boswell,6 Ihor Bekersky,6 Ala Alak,6 Donald Buell,6 John Barret,7 and Wyndham Wilson8

Pediatric Oncology Branch1 and Medicine Branch,8 National Cancer Institute, Nursing Department,4 and Department of Pharmacy,5 Warren Grant Magnuson Clinical Center, and National Heart, Lung, and Blood Institute,7 National Institutes of Health, Bethesda, Maryland; Loyola University Medical Center,2 and Fujisawa, USA,6 Chicago, Illinois; and Children's National Medical Center, Washington, D.C.3

Received 30 June 1997/Returned for modification 17 October 1997/Accepted 3 May 1998

The safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) administered for empirical antifungal therapy were evaluated for 36 persistently febrile neutropenic adults receiving cancer chemotherapy and bone marrow transplantation. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study which enrolled a total of 8 to 12 patients in each of the four dosage cohorts. Each cohort received daily doses of either 1.0, 2.5, 5.0, or 7.5 mg of amphotericin B in the form of AmBisome/kg of body weight. The study population consisted of patients between the ages of 13 and 80 years with neutropenia (absolute neutrophil count, <500/mm3) who were eligible to receive empirical antifungal therapy. Patients were monitored for safety and tolerance by frequent laboratory examinations and the monitoring of infusion-related reactions. Efficacy was assessed by monitoring for the development of invasive fungal infection. The pharmacokinetic parameters of AmBisome were measured as those of amphotericin B by high-performance liquid chromatography. Noncompartmental methods were used to calculate pharmacokinetic parameters. AmBisome administered as a 1-h infusion in this population was well tolerated and was seldom associated with infusion-related toxicity. Infusion-related side effects occurred in 15 (5%) of all 331 infusions, and only two patients (5%) required premedication. Serum creatinine, potassium, and magnesium levels were not significantly changed from baseline in any of the dosage cohorts, and there was no net increase in serum transaminase levels. AmBisome followed a nonlinear dosage relationship that was consistent with reticuloendothelial uptake and redistribution. There were no breakthrough fungal infections during empirical therapy with AmBisome. AmBisome administered to febrile neutropenic patients in this study was well tolerated, was seldom associated with infusion-related toxicity, was characterized by nonlinear saturation kinetics, and was effective in preventing breakthrough fungal infections.

* Corresponding author. Mailing address: NCI/POB/IHS, Bldg. 10, Rm. 13N-240, Bethesda, MD 20892. Phone: (301) 402-0023. Fax: (301) 402-0575. E-mail: walsht{at}pbmac.nci.nih.gov.

Antimicrobial Agents and Chemotherapy, September 1998, p. 2391-2398, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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