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

Abstract

PURPOSE:

The pharmacokinetics (PK), biodistribution and therapeutic efficacy of cisplatin encapsulated in long-circulating pegylated (Stealth) liposomes (SPI-077) were compared with those of nonliposomal cisplatin in two murine (C26 colon carcinoma and Lewis lung) tumor models.

METHODS:

In therapeutic 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 study, mice received a single intravenous bolus injection of 3 mg/kg of either 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 graphite furnace (flameless) atomic absorption spectrophotometery (GF-AAS).

RESULTS:

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 lung tumors, equivalent SPI-077 antitumor activity was seen at only half the cisplatin dose. Higher cumulative doses of SPI-077 were well tolerated and had increased antitumor effect. SPI-077 PK were characterized by a one-compartment model with nonlinear (saturable) elimination, whereas cisplatin PK were described by a two-compartment model with linear elimination. SPI-077 had a 55-fold lower [corrected] volume of distribution, 3-fold higher peak plasma levels, and a 60-fold larger plasma AUC compared with cisplatin. In addition, SPI-077-treated animals displayed a 4-fold reduction in Pt delivered to the kidneys (primary target organ of toxicity) relative to cisplatin, but a 28-fold higher tumor AUC than cisplatin.

CONCLUSIONS:

Based on the results of our studies, encapsulation of cisplatin in long-circulating pegylated liposomes has overcome limitations experienced with other liposomal cisplatin formulations. 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.

• Authors: M S Newman, G T Colbern, P K Working, C Engbers, M A Amantea
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 43 Issue 1 Pg. 1-7 ( 1999) ISSN: 0344-5704 [Print] Germany
• PMID: 9923534 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Antineoplastic Agents
• Drug Carriers
• Liposomes
• Cisplatin

Topics

• Algorithms
• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics, pharmacology)
• Carcinoma, Lewis Lung (drug therapy, metabolism)
• Cisplatin (administration & dosage, pharmacokinetics, pharmacology)
• Colonic Neoplasms (drug therapy, metabolism)
• Drug Carriers
• Injections, Intravenous
• Liposomes
• Mice
• Mice, Inbred BALB C
• Neoplasm Transplantation
• Rats
• Spectrophotometry, Atomic
• Tissue Distribution