Abstract 4653: Pharmacokinetics and biodistribution of eribulin mesylate, paclitaxel, and ixabepilone in mouse

Abstract

Abstract Chemotherapy-induced peripheral neurotoxicity is a major clinical problem representing the dose-limiting side effect of many antineoplastic drugs. The degree and type of neuropathy incurred is dependent on the chemotherapeutic drug, dose intensity, and cumulative dose. In an earlier study by our group, we found that paclitaxel and ixabepilone, administered to mice at their respective MTDs, produced dose dependent deficits in caudal nerve conduction velocity, caudal amplitude and digital nerve amplitudes, as well as moderate to severe degenerative pathologic changes in dorsal root ganglia (DRG) and sciatic nerve (SN). In contrast, eribulin mesylate produced no significant deleterious effects on any nerve conduction parameter measured and caused milder, less frequent effects on morphology. Similar trends for eribulin to cause less neuropathy (including later onset and resolution) in the clinic have also been reported (Cigler and Vadhat, 2010; Jain and Cigler 2012, Vadhat et al., 2013). Differences in tubulin binding may, in part, potentially explain the differential effect (Perez et al 2009; Jordan et al 2005). Another potential explanation may reside in different pharmacokinetic (PK) and peripheral nerve distribution of these agents. To elucidate this, mice received a single dose of paclitaxel, ixabepilone or eribulin mesylate (30, 3 and 1.75mg/kg respectively, based on an MTD regimen), administered IV into the caudal vein. Plasma, DRG and SN samples were obtained at 0.25, 1, 3, 6, 8, 24, 48, and 72 h post dose. Tissues were homogenized and after extraction, concentrations of eribulin mesylate, ixabepilone and paclitaxel were determined in each matrix using LC/MS/MS. PK parameters were calculated using noncompartmental analysis in WinNonLin v 5.0.3. We report that all 3 chemotherapies rapidly penetrated both SN and DRG with maximal concentrations seen at, or within 15 mins after administration. Concentrations of all 3 agents in DRG and SN then declined by 30-50% over the first 1-3h and thereafter remained relatively stable in the tissue for up to 72 h, despite clearing rapidly from plasma to reach levels below quantification, (<5 ng/ml), by 24 h. Overall, dose normalized AUC in SN was similar for eribulin mesylate and ixabepilone and higher than for paclitaxel (1927 vs 2451 vs 793 ng/h/per g tissue, respectively). The ranking for the dose normalized AUC in DRG was eribulin mesylate < paclitaxel < ixabepilone (3894 vs 7217 vs 22800 ng/h/per g tissue, respectively). These findings suggest that peripheral nerve exposure is likely not the underlying mechanism for the differential propensity of eribulin mesylate, paclitaxel and ixabepilone to produce neurotoxicity. This work was financially supported by Eisai. Citation Format: Krystyna Wozniak, Ying Wu, Kenichi Nomoto, Bruce A. Littlefield, Christopher DesJardins, Edgar Schuck, Phil Saxton, Nancy Wong, Barbara S. Slusher. Pharmacokinetics and biodistribution of eribulin mesylate, paclitaxel, and ixabepilone in mouse. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4653. doi:10.1158/1538-7445.AM2014-4653