Safety, toxicokinetics and tissue distribution of long-term intravenous liposomal amphotericin B (AmBisome (R)): A 91-day study in rats

Purpose. Amphotericin B in small, unilamellar liposomes (AmBisome(R)) is sa fer and produces higher plasma concentrations than other formulations. Beca use liposomes may increase and prolong tissue exposures. the potential for drug accumulation or delayed toxicity after chronic AmBisome was investigat ed. Methods, Rats(174/sex) received intravenous AmBisome (1, 4, or 12 mg/kg). d extrose. or empty liposomes for 91 days with a 30-day recovery. Safety (inc luding 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. Nephrotoxi city was moderate (urean nitrogen [BUN] less than or equal to 51 mg/ dl: cr eatinine: unchanged). Liposome-related changes (vacuolated macrophages and hypercholesterolemia) were also observed. Although plasma and tissue accumu lation was nonlinear and progressive (clearance and volume decreased, half- life increased with dose and time), most toxic changes occurred early, stab ilized by the end of dosing, and reversed during recovery. There were no de layed 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 mug/ml and tissue levels >3000 mug/g.