Safety, toxicokinetics and tissue distribution of long-term intravenous liposomal amphotericin B (AmBisome): a 91-day study in rats.
OBJECTIVE
Amphotericin B in small, unilamellar liposomes (AmBisome) is safer and produces higher plasma concentrations than other formulations. Because liposomes may increase and prolong tissue exposures, the potential for drug accumulation or delayed toxicity after chronic AmBisome was investigated.


METHODS
Rats (174/sex) received intravenous AmBisome (1, 4, or 12 mg/kg), dextrose, or empty liposomes for 91 days with a 30-day recovery. Safety (including clinical and microscopic pathology) and toxicokinetics in plasma and tissues were evaluated.


RESULTS
Chemical and histopathologic changes demonstrated that the kidneys and liver were the target organs for chronic AmBisome toxicity. Nephrotoxicity was moderate (urean nitrogen [BUN] < or = 51 mg/dl; creatinine unchanged). Liposome-related changes (vacuolated macrophages and hypercholesterolemia) were also observed. Although plasma and tissue accumulation was nonlinear and progressive (clearance and volume decreased, half-life increased with dose and time), most toxic changes occurred early, stabilized by the end of dosing, and reversed during recovery. There were no delayed toxicities. Concentrations in liver and spleen greatly exceeded those in plasma: kidney and lung concentrations were similar to those in plasma. Elimination half-lives were 1-4 weeks in all tissues.


CONCLUSIONS
Despite nonlinear accumulation, AmBisome revealed predictable hepatic and renal toxicities after 91 days, with no new or delayed effects after prolonged treatment at high doses that resulted in plasma levels >200 microg/ml and tissue levels >3000 microg/g.
Bekersky
I
I
Fujisawa Healthcare Inc, Deerfield, IL, USA. ihor_bekersky@fujisawa.com
Boswell
G W
GW
Hiles
R
R
Fielding
R M
RM
Buell
D
D
Walsh
T J
TJ
D000666:Amphotericin B / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D019540:Area Under Curve; D001772:Blood Cell Count; D001774:Blood Chemical Analysis; D001806:Blood Urea Nitrogen; D003692:Delayed-Action Preparations; D005260:Female; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000935:Antifungal Agents; D003692:Delayed-Action Preparations; C068538:liposomal amphotericin B; D000666:Amphotericin B