Safety and toxicokinetics of intravenous liposomal amphotericin B (AmBisome (R)) in beagle dogs

Purpose. Amphotericin B (AmB) in small, unilamellar liposomes (AmBisome(R)) has an improved therapeutic index, and altered pharmacokinetics. The repea t-dose safety and toxicokinetic profiles of AmBisome were studied at clinic ally relevant doses. Methods. Beagle dogs (5/sex/group) received intravenous AmBisome (0.25, 1, 4, 8, and 16 mg/kg/day), empty liposomes or vehicle for 30 days. AmB was de termined in plasma on days 1, 14, and 30, and in tissues on day 31. Safety parameters included body weight, clinical chemistry, hematology and microsc opic pathology. Results. Seventeen of twenty animals receiving 8 and 16 mg/kg were sacrific ed early due to weight loss caused by reduced food intake. Dose-dependent r enal tubular nephrosis, and other effects characteristic of conventional Am B occurred at 1 mg/kg/day or higher. Although empty liposomes and AmBisome increased plasma cholesterol, no toxicities unique to AmBisome were reveale d. Plasma ultrafiltrates contained no AmB. AmBisome achieved plasma levels 100-fold higher than other AmB formulations. AmBisome kinetics were non-lin ear, with clearance and distribution volumes decreasing with increasing dos e. This, and nonlinear tissue uptake, suggest AmBisome disposition was satu rable. Conclusions. AmBisome has the same toxic effects as conventional AmB, but t hey appear at much higher plasma exposures. AmBisome's non-linear pharmacok inetics are not associated with increased risk, as toxicity increases linea rly with dosage. Dogs tolerated AmBisome with minimal to moderate changes i n renal function at doses (4 mg/kg/day) producing peak plasma concentration s of 18-94 mu g/mL.