Abstract 5469: Pharmacokinetics and activity of nanoliposomal irinotecan (MM-398) against Ewings Sarcoma xenografts are superior to the conventional irinotecan formulation

Abstract

Abstract Background: Irinotecan (CPT-11) is an antineoplastic prodrug, of which SN-38 is an active metabolite. Liposomal CPT-11 was developed to improve systemic and tumor exposure to CPT-11 and its active metabolite by reducing the exposure of CPT-11 to neutral and basic pH, in which CPT-11 is hydrolyzed into an inactive carboxylate form. The aims of the current study are 1) to compare the plasma and tissue/tumor pharmacokinetics of nanoliposomal CPT-11 (in clinical trials as PEP02 or MM-398) and conventional irinotecan in mice, and 2) to compare anti-tumor activity of the two formulations against Ewings Sarcoma murine xenografts. Methods: An assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed to measure CPT-11 and SN-38 concentrations in plasma and tissue. Plasma and tissue pharmacokinetics of liposomal and conventional irinotecan were characterized in Balb/c mice (non-tumor bearing); pharmacokinetics and activity were assessed in athymic nu/nu mice xenografted with human Ewings sarcoma. Results: Following a 20 mg/kg dose of intravenous liposomal irinotecan, both plasma and tumor concentrations of CPT-11 and SN-38 were approximately 10-fold higher than conventional irinotecan. The Cmax and AUC were dose-proportionally increased after a single dose of liposomal irinotecan in non-tumor bearing mice. In mice xenografted with Ewings sarcoma (CHLA-258), liposomal irinotecan significantly extended event-free survival of mice compared with controls or conventional irinotecan (P<0.05). Conclusions: Our data demonstrate that 1) liposomal CPT-11 achieves higher plasma and tissue concentrations with longer duration compared with conventional irinotecan, and that 2) liposomal formulation has greater anti-tumor activity relative to conventional irinotecan. These results suggest that liposomal irinotecan may provide improved anti-tumor activity over conventional irinotecan by increasing systemic and tumor exposures to the SN-38 active metabolite. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5469. doi:10.1158/1538-7445.AM2011-5469