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Antimicrobial Agents and Chemotherapy, December 2001, p. 3487-3496, Vol. 45, No. 12
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.12.3487-3496.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Safety, Tolerance, and Pharmacokinetics of High-Dose Liposomal Amphotericin B (AmBisome) in Patients Infected with Aspergillus Species and Other Filamentous Fungi: Maximum Tolerated Dose Study

Thomas J. Walsh,1,* Jesse L. Goodman,2 Peter Pappas,3 Ihor Bekersky,4 Donald N. Buell,4 Maureen Roden,1 John Barrett,5 and Elias J. Anaissie6

Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute,1 and National Heart, Lung, and Blood Institute,5 Bethesda, Maryland; Division of Infectious Diseases, Department of Medicine, University of Minnesota School of Medicine, Minneapolis, Minnesota2; Division of Infectious Diseases, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama3; Fujisawa Healthcare, Inc., Deerfield, Illinois4; and Myeloma and Transplantation Research Center, Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas6

Received 7 March 2001/Returned for modification 21 July 2001/Accepted 21 September 2001

We conducted a phase I-II study of the safety, tolerance, and plasma pharmacokinetics of liposomal amphotericin B (L-AMB; AmBisome) in order to determine its maximally tolerated dosage (MTD) in patients with infections due to Aspergillus spp. and other filamentous fungi. Dosage cohorts consisted of 7.5, 10.0, 12.5, and 15.0 mg/kg of body weight/day; a total of 44 patients were enrolled, of which 21 had a proven or probable infection (13 aspergillosis, 5 zygomycosis, 3 fusariosis). The MTD of L-AMB was at least 15 mg/kg/day. Infusion-related reactions of fever occurred in 8 (19%) and chills and/or rigors occurred in 5 (12%) of 43 patients. Three patients developed a syndrome of substernal chest tightness, dyspnea, and flank pain, which was relieved by diphenhydramine. Serum creatinine increased two times above baseline in 32% of the patients, but this was not dose related. Hepatotoxicity developed in one patient. Steady-state plasma pharmacokinetics were achieved by day 7. The maximum concentration of drug in plasma (Cmax) of L-AMB in the dosage cohorts of 7.5, 10.0, 12.5, and 15.0 mg/kg/day changed to 76, 120, 116, and 105 µg/ml, respectively, and the mean area under the concentration-time curve at 24 h (AUC24) changed to 692, 1,062, 860, and 554 µg · h/ml, respectively, while mean CL changed to 23, 18, 16, and 25 ml/h/kg, respectively. These data indicate that L-AMB follows dose-related changes in disposition processing (e.g., clearance) at dosages of >= 7.5 mg/kg/day. Because several extremely ill patients had early death, success was determined for both the modified intent-to-treat and evaluable (7 days of therapy) populations. Response rates (defined as complete response and partial response) were similar for proven and probable infections. Response and stabilization, respectively, were achieved in 36 and 16% of the patients in the modified intent-to-treat population (n = 43) and in 52 and 13% of the patients in the 7-day evaluable population (n = 31). These findings indicate that L-AMB at dosages as high as 15 mg/kg/day follows nonlinear saturation-like kinetics, is well tolerated, and can provide effective therapy for aspergillosis and other filamentous fungal infections.

* Corresponding author. Mailing address: Immunocompromised Host Section, National Cancer Institute, Building 10, Rm. 13N240, Bethesda, MD 20892. Phone: (301) 402-0023. Fax: (301) 402-0575. E-mail: walsht{at}mail.nih.gov.

Antimicrobial Agents and Chemotherapy, December 2001, p. 3487-3496, Vol. 45, No. 12
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.12.3487-3496.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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