SAFETY, TOLERANCE, AND PHARMACOKINETICS OF A SMALL UNILAMELLAR LIPOSOMAL FORMULATION OF AMPHOTERICIN-B (AMBISOME) IN NEUTROPENIC PATIENTS

The safety, tolerance, and pharmacokinetics of a small unilamellar lip osomal formulation of amphotericin B (AmBisome) administered for empir ical antifungal therapy were evaluated for 36 persistently febrile neu tropenic adults receiving cancer chemotherapy and bone marrow transpla ntation. The protocol was an open-label, sequential-dose-escalation, m ultidose pharmacokinetic study which enrolled a total of 8 to 12 patie nts in each of the four dosage cohorts. Each cohort received daily dos es 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 patient s between the ages of 13 and 80 years with neutropenia (absolute neutr ophil count, <500/mm(3)) who were eligible to receive empirical antifu ngal therapy. Patients were monitored for safety and tolerance by freq uent laboratory examinations and the monitoring of infusion-related re actions. Efficacy was assessed by monitoring for the development of in vasive fungal infection. The pharmacokinetic parameters of AmBisome we re measured as those of amphotericin B by high-performance liquid chro matography. Noncompartmental methods were used to calculate pharmacoki netic parameters. AmBisome administered as a l-h infusion in this popu lation was well tolerated and was seldom associated with infusion-rela ted toxicity. Infusion-related side effects occurred in 15 (5%) of all 331 infusions, and only two patients (5%) required premedication. Ser um creatinine, potassium, and magnesium levels,were not significantly changed from baseline in any of the dosage cohorts, and there was no n et increase in serum transaminase levels. AmBisome followed a nonlinea r dosage relationship that was consistent with reticuloendothelial upt ake and redistribution. There were no breakthrough fungal infections d uring empirical therapy with AmBisome. AmBisome administered to febril e neutropenic patients in this study was well tolerated, was seldom as sociated,vith infusion-related toxicity, was characterized by nonlinea r saturation kinetics, and was effective in preventing breakthrough fu ngal infections.