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 (C(max)) 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 microg/ml, respectively, and the mean area under the concentration-time curve at 24 h (AUC(24)) changed to 692, 1,062, 860, and 554 microg x 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 >or=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.