Eribulin shows high concentration and long retention in xenograft tumor tissues

PURPOSE: Eribulin, a synthetic analog of the natural product halichondrin B, is a microtubule dynamics inhibitor. In this study, we report the pharmacokinetic profiles of eribulin in mice, rats, and dogs following intravenous administrations with optimized and validated bio-analytical methods. METHODS: Eribulin was administered at 0.5 and 2 mg/kg in mice, 0.5 and 1 mg/kg in rats, and 0.08 mg/kg in dogs. Tumor and brain penetration of eribulin was also evaluated in LOX human melanoma xenograft models. Concentrations in plasma, tumor, and brain were measured by the LC–MS/MS method. RESULTS: The profiles of eribulin were characterized by extensive distribution, moderate clearance, and slow elimination in the three species. The pharmacokinetics are linear in mice and rats. In xenograft mice, the penetration into the brain was low, as expected, since eribulin is a P-glycoprotein substrate. In contrast to disposition in brain, the exposure of eribulin was approximately 20–30 times higher in tumor than that in plasma and half-lives were 17.8–35.9 h after both single and multiple dose regimens. CONCLUSIONS: Eribulin was distributed rapidly and eliminated slowly in mice, rats, and dogs. The exposure of eribulin was approximately 20–30 times higher in tumor than in plasma in xenograft mice. These results might be caused by eribulin’s mechanism of action including increased perfusion in tumor by vascular remodeling effect.