Abstract
Abstract E7389 (eribulin mesylate, Halaven, Eisai) is a fully synthetic analog of the marine sponge natural product halichondrin B. It has been approved in US and more than 50 countries worldwide for treatment of advanced breast cancer. To improve the therapeutic index of E7389, a liposomal formulation of E7389, E7389-LF is under development. In this study, we characterized the pharmacokinetics of E7389-LF and E7389 (aqueous formulation) in mice and evaluated the anti-tumor activity of E7389-LF and E7389 in mouse xenograft model. In general the pharmacokinetics of E7389-LF was characterized by a small volume of distribution, slow clearance, and slow elimination in all liposomal formulations tested. Plasma AUC of E7389-LF was more than 600 fold larger than that of E7389 in tumor bearing mice. Tumor AUC of E7389-LF was also observed. Moreover, free E7389 (not liposome encapsulated and not protein bound) was measured in mouse plasma by ultracentrifugation method. The concentration ratio of E7389 in ultracentrifuged mouse plasma (UCM) vs E7389 in plasma after a 2 mg/kg i.v. of E7389 ranged from 54.19% to 65.41%, which was similar to the free fraction in the mouse plasma. The respective concentration ratio of E7389 in UCM vs E7389 in plasma after a 2 mg/kg i.v. of E7389-LF ranged from 0.07% to 0.59%, and the exposure, expressed as AUC, of UCM/plasma ratio was determined to be 0.2%. The free E7389 exposure, measured by UCM, after E7389-LF administration was about 1.5 fold of that after E7389 administration. Anti-tumor activity of E7389-LF and E7389 was evaluated in a human pharynx carcinoma, FaDu, xenograft model. E7389-LF showed dose-dependent anti-tumor effect with regression of tumors at 2.5 mg/kg dose, which was significantly better than that after E7389 administration in this model. These findings suggest that E7389-LF showed better anti-tumor activity than that of E7389 in human FaDu xenograft mouse model. Citation Format: Makoto Asano, Kenji Hyodo, Yanke Yu, Edgar Schuck, Junji Matsui, Hiroshi Ishihara, Hiroshi Kikuchi, Kenichi Nomoto. Characterization of the liposomal formulation of eribulin mesylate (E7389) in mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4543. doi:10.1158/1538-7445.AM2015-4543
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