Comparative pharmacokinetics, tissue distribution, and therapeutic effectiveness of cisplatin encapsulated in long-circulating, pegylated liposomes (SPI-077) in tumor-bearing mice

Purpose: The pharmacokinetics (PK), biodistribution and therapeutic efficac y of cisplatin encapsulated in long-circulating pegylated (Stealth(R)) lipo somes (SPI-077) were compared with those of nonliposomal cisplatin in two m urine (C26 colon carcinoma and Lewis lung) tumor models. Methods: III thera peutic effectiveness studies, mice bearing murine C26 or Lewis lung tumors received multiple intravenous doses of SPI-077 or cisplatin in a variety of treatment schedules and cumulative doses. In the PK and biodistribution st udy, mice received a single intravenous bolus injection of 3 mg/kg of eithe r SPI-077 or cisplatin 14 days after inoculation with 10(6) C26 tumor cells . Plasma and tissues were analyzed for total platinum (Pt) content by graph ite furnace (flameless) atomic absorption spectro-photometery (GF-AAS). Res ults: Efficacy studies showed that SPI-077 had superior antitumor activity compared to the same cumulative dose of cisplatin. When lower doses of SPI- 077 were compared to cisplatin at its maximally tolerated dose in Lewis lun g tumors, equivalent SPI-077 antitumor activity was seen at only half the c isplatin dose. Higher cumulative doses of SPI-077 were well tolerated and h ad increased antitumor effect. SPI-077 PK were characterized by a one-compa rtment model with nonlinear (saturable) elimination, whereas cisplatin PK w ere described by a two-compartment model with linear elimination. SPI-077 h ad a 55-fold higher volume of distribution, 3-fold higher peak plasma level s, and a 60-fold larger plasma AUC compared with cisplatin. In addition, SP I-077-treated animals displayed a 4-fold reduction in Pt delivered to the k idneys (primary target organ of toxicity) relative to cisplatin, but a 28-f old higher tumor AUC than cisplatin. Conclusions: Based on the results of o ur studies, encapsulation of cisplatin in long-circulating pegylated liposo mes has overcome limitations experienced with other liposomal cisplatin for mulations. SPI-077 has a prolonged circulation time and increased tumor Pt disposition, and its antitumor effect is significantly improved compared to cisplatin in murine colon and lung cancer models.