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Neuropathy-inducing effects of eribulin mesylate versus paclitaxel in mice with preexisting neuropathy
Krystyna M Wozniak1, Ying Wu, Mohamed H Farah
1NeuroTranslational Drug Discovery Program, Brain Science Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Abstract:
Eribulin mesylate (E7389, INN:eribulin mesilate Halaven(®)) is a non-taxane microtubule dynamics inhibitor currently in clinical use for advanced breast cancer. Other microtubule-targeting agents for breast cancer, including paclitaxel and ixabepilone, display a common treatment dose-limiting toxicity of peripheral neuropathy (PN). In an earlier study, we found eribulin mesylate had a lower propensity to induce PN in mice than either paclitaxel or ixabepilone. In the current study, we compared additional PN induced by paclitaxel versus eribulin mesylate when administered to mice with preexisting paclitaxel-induced PN. Initially, paclitaxel at 0.75 × its maximum tolerated dose (MTD; 22.5 mg/kg) was given on a Q2Dx3 regimen for 2 weeks. The second chemotherapy was 0.5 MTD eribulin mesylate (0.875 mg/kg) or paclitaxel (15 mg/kg) on a similar regimen, starting 2 weeks after the first. Initial paclitaxel treatment produced significant decreases in caudal nerve conduction velocity (NCV; averaging 19.5 ± 1 and 22.2 ± 1.3 %, p < 0.001) and amplitude (averaging 53.2 ± 2.6 and 72.4 ± 2.1 %, p < 0.001) versus vehicle when measured 24 h or 2 weeks after dosing cessation, respectively. Additional 0.5 MTD paclitaxel further reduced caudal NCV and amplitude relative to immediately before initiation of the second regimen (by 11 ± 2.1 and 59.2 ± 5 %, p < 0.01, respectively). In contrast, 0.5 MTD eribulin mesylate caused no further decrease in caudal NCV. In conclusion, unlike additional paclitaxel treatment, eribulin mesylate administered to mice with preexisting paclitaxel-induced PN had limited additional deleterious effects at 6 weeks. These preclinical data suggest that eribulin mesylate may have reduced tendency to exacerbate preexisting paclitaxel-induced PN in clinical settings.
Insights
Eribulin mesylate shows less worsening of existing peripheral neuropathy (PN) in mice compared to additional paclitaxel. This suggests eribulin may be a safer option for breast cancer patients with prior PN.
Area of Science:
- Oncology
- Pharmacology
- Neuroscience
Background:
- Eribulin mesylate is a microtubule inhibitor used for advanced breast cancer.
- Peripheral neuropathy (PN) is a common dose-limiting toxicity for microtubule agents like paclitaxel.
- Previous studies indicated eribulin mesylate has a lower propensity to induce PN.
Purpose of the Study:
- To compare the effects of additional paclitaxel versus eribulin mesylate on preexisting paclitaxel-induced peripheral neuropathy (PN) in mice.
- To evaluate the potential of eribulin mesylate to exacerbate PN in a preclinical model.
Main Methods:
- Mice received initial paclitaxel treatment, inducing significant decreases in nerve conduction velocity and amplitude.
- Following a 2-week recovery, mice received either additional paclitaxel or eribulin mesylate.
- Nerve conduction parameters were measured to assess additional PN induction.
Main Results:
- Additional paclitaxel significantly worsened nerve conduction velocity and amplitude in mice with preexisting PN.
- Eribulin mesylate did not cause further decreases in nerve conduction velocity.
- Eribulin mesylate showed limited additional deleterious effects on PN at 6 weeks.
Conclusions:
- Eribulin mesylate may have a reduced tendency to exacerbate preexisting paclitaxel-induced PN.
- These preclinical findings suggest potential clinical benefits for eribulin mesylate in managing PN.
- Further clinical investigation is warranted to confirm eribulin's safety profile in patients with prior PN.