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

Abstract

The toxicity of cisplatin encapsulated in pegylated, long-circulating liposomes (SPI-077) was compared with nonliposomal cisplatin in male and female cynomolgus monkeys (n = 2-4 per sex per group) treated with intravenous infusions 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 survived until scheduled necropsy at 3 days after the final treatment or after a treatment-free 4-week recovery period. Emesis occurred after each treatment in all cisplatin-treated monkeys, but only once in one monkey treated with high-dose SPI-077. Dose-related mild decreases in red blood cell (RBC) count, hemoglobin, and hematocrit to or slightly below low normal range occurred in the high-dose SPI-077 and placebo liposome treatment groups after each treatment, with partial to complete recovery between treatments and no signs of correlating bone marrow toxicity. Decreases were similar in cisplatin-treated monkeys, but resolved only slightly between treatments and after the end of treatment (continuing to decrease in females) and were accompanied by bone marrow hypocellularity. Indirect, but not direct, bilirubin levels were cyclically elevated in the high-dose SPI-077 and placebo-treated animals, but not in the other treatment groups. Levels had either fully resolved or were near baseline and/or saline group values prior to the next treatment. 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 considered related to the lipid dose administered. Cisplatin-treated monkeys exhibited sensory polyneuropathy and moderate irreversible toxic tubular nephrosis, but no neuropathy or nephrotoxicity was seen in either SPI-077 treatment group. Microscopically, treatment-related cell death was seen in dorsal root ganglia (DRG), affecting 15% of the cells in cisplatin-treated animals, compared to 8 and 12% in the low- and high-dose SPI-077 treatment groups. Neither drug was ototoxic. In summary, repeated administration of SPI-077 produced minimal, reversible effects related to the lipid dose administered, mostly limited to the 25 mg/kg dose group. The most notable effects in this group were cyclical decreases in hematology parameters thought to be related to increased recycling of a small fraction of RBCs and limited cell death in the DRG in the absence of any neurophysiological changes. Animals 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 cisplatin may provide a less toxic alternative to standard cisplatin solution.