title: Safety and toxicokinetics of intravenous liposomal amphotericin B (AmBisome) in beagle dogs.
abstract: OBJECTIVE
  Amphotericin B (AmB) in small, unilamellar liposomes (AmBisome) has an improved therapeutic index, and altered pharmacokinetics. The repeat-dose safety and toxicokinetic profiles of AmBisome were studied at clinically 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 determined in plasma on days 1, 14, and 30, and in tissues on day 31. Safety parameters included body weight, clinical chemistry, hematology and microscopic pathology.
  
  
  RESULTS
  Seventeen of twenty animals receiving 8 and 16 mg/kg were sacrificed early due to weight loss caused by reduced food intake. Dose-dependent renal tubular nephrosis, and other effects characteristic of conventional AmB occurred at 1 mg/kg/day or higher. Although empty liposomes and AmBisome increased plasma cholesterol, no toxicities unique to AmBisome were revealed. Plasma ultrafiltrates contained no AmB. AmBisome achieved plasma levels 100-fold higher than other AmB formulations. AmBisome kinetics were non-linear, with clearance and distribution volumes decreasing with increasing dose. This, and nonlinear tissue uptake, suggest AmBisome disposition was saturable.
  
  
  CONCLUSIONS
  AmBisome has the same toxic effects as conventional AmB, but they appear at much higher plasma exposures. AmBisome's non-linear pharmacokinetics are not associated with increased risk, as toxicity increases linearly with dosage. Dogs tolerated AmBisome with minimal to moderate changes in renal function at doses (4 mg/kg/day) producing peak plasma concentrations of 18-94 microg/mL.
authors.affiliation: Fujisawa Healthcare Inc., Deerfield, Illinois 60015-2548, USA. ihor_bekersky@fujisawa.com
authors.forename: I
authors.initials: I
authors.lastname: Bekersky
authors.forename: G W
authors.initials: GW
authors.lastname: Boswell
authors.forename: R
authors.initials: R
authors.lastname: Hiles
authors.forename: R M
authors.initials: RM
authors.lastname: Fielding
authors.forename: D
authors.initials: D
authors.lastname: Buell
authors.forename: T J
authors.initials: TJ
authors.lastname: Walsh
mesh_terms: D000666:Amphotericin B / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D000935:Antifungal Agents / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D001772:Blood Cell Count / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004285:Dogs; D005260:Female; D007262:Infusions, Intravenous; D007668:Kidney / Q000473:pathology; D008081:Liposomes; D008297:Male; D011897:Random Allocation; D013997:Time Factors; D014018:Tissue Distribution; D016482:Urinalysis
chemical_list: D000935:Antifungal Agents; D008081:Liposomes; C068538:liposomal amphotericin B; D000666:Amphotericin B