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

Abstract

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.

Amphotericin B Formulations and Drug Targeting

“…122 At high doses there is non-linear clearance with saturation of the reticuloendothelial system and redistribution of the drug in other tissues. 123 Differences in the action of the reticuloendothelial system between individuals can be the reason for the higher intersubject variability of AmBisome 1 pharmacokinetic parameter, 40-75% of relative standard deviation, in comparison with 15-25% obtained with Fungizone 1 . 100 The profile of AmBisome 1 is reported to be superior to that of Fungizone 1 .…”

Development of polyion complex micelles for encapsulating and delivering amphotericin B

“…Unlike the deoxycholate formulation, the second type is a lipid-based formulation with low nephrotoxicity [4,5]. However, cost and other factors limit its widespread use [6][7][8]. Much effort has been made to develop costeffective delivery systems with reduced AmB toxicity.…”

Caspofungin as First-Line Therapy for the Treatment of Invasive Aspergillosis After Thoracic Organ Transplantation

“…2 The introduction of liposomal formulations of amphotericin B could reduce, but not eliminate these adverse events completely. 2,3 Azole derivatives such as itraconazole and the recently introduced voriconazole demonstrated acceptable or good efficacy against Aspergillus and were better tolerated. 4 -7 Azoles, however, are substrates for and inhibitors of cytochrome 450.…”