Comparative intravenous toxicity of cisplatin solution and cisplatin encapsulated in long-circulating, pegylated liposomes in cynomolgus monkeys

The toxicity of cisplatin encapsulated in pegylated, long-circulating lipos omes (SPI-077) was compared with nonliposomal cisplatin in male and female cynomolgus monkeys (n = 2-4 per sex per group) treated with intravenous inf usions of 2.5 or 25 mg/kg SPI-077, 2.5 mg/kg cisplatin, placebo liposomes, or saline once every 3 weeks for total of five treatments. All animals surv ived until scheduled necropsy at 3 days after the final treatment or after a treatment-free 4-week recovery period. Emesis occurred after each treatme nt in all cisplatin-treated monkeys, but only once in one monkey treated wi th high-dose SPI-077. Dose-related mild decreases in red blood cell (RBC) c ount, hemoglobin, and hematocrit to or slightly below low normal range occu rred in the high-dose SPI-077 and placebo liposome treatment groups after e ach treatment, with partial to complete recovery between treatments and no signs of correlating bone marrow toxicity. Decreases were similar in cispla tin-treated monkeys, but resolved only slightly between treatments and afte r the end of treatment (continuing to decrease in females) and were accompa nied by bone marrow hypocellularity. Indirect, but not direct, bilirubin le vels were cyclically elevated in the high-dose SPI-077 and placebo-treated animals, but not in the other treatment groups. Levels had either fully res olved or were near baseline and/or saline group values prior to the next tr eatment. Serum cholesterol levels were cyclically increased in SPI-077- and placebo liposome-treated animals, and minimally increased numbers of foam cells were seen in the liver, spleen, kidney, and other organs; both were c onsidered related to the lipid dose administered. Cisplatin-treated monkeys exhibited sensory polyneuropathy and moderate irreversible toxic tubular n ephrosis, but no neuropathy or nephrotoxicity was seen in either SPI-077 tr eatment group. Microscopically, treatment-related cell death was seen in do rsal root ganglia (DRG), affecting 15% of the cells in cisplatin-treated an imals, compared to 8 and 12% in the low- and high-dose SPI-077 treatment gr oups. Neither drug was ototoxic. In summary, repeated administration of SPI -077 produced minimal, reversible effects related to the lipid dose adminis tered, mostly limited to the 25 mg/kg dose group. The most notable effects in this group were cyclical decreases in hematology parameters thought to b e related to increased recycling of a small fraction of RBCs and limited ce ll death in the DRG in the absence of any neurophysiological changes. Anima ls treated with a 10-fold lower dose of cisplatin (2.5 mg/kg), in contrast, exhibited myelo-, nephro-, and neurotoxicity, including sensory neuropathy , and were emetic after every dose. The SPI-077 liposomal formulation of ci splatin may provide a less toxic alternative to standard cisplatin solution . (C) 1998 Society of Toxicology.