Clinical and non-clinical formulations of paclitaxel produce qualitatively and quantitatively different peripheral...

Paclitaxel-induced peripheral neuropathy (PIPN) is a common side effect after treatment with paclitaxel, a chemotherapy medication used for solid-tumor cancers. Preclinical studies of PIPN using rodents have focused on male rats and demonstrated a high variability in behavioral outcomes. Here we report a simple, robust, reproducible PIPN protocol that is fast-acting, effective over the course of 3 weeks, and efficacious in both male and female cohorts of inbred mouse and outbred rat strains. Mechanoreceptive and thermoreceptive behavioral outcomes were measured using standard von Frey, Hargreaves, and cold plate assays, respectively. We compared a standard, commercially-available paclitaxel to a clinical formulation used in human patients and found the clinical formulation caused behavioral effects lasting 3-4 weeks longer than commercially-available paclitaxel. Pharmacokinetic analysis revealed higher plasma drug exposure pattern for the clinical formulation, which can partially explain differences observed between formulations. PERSPECTIVE: This article documents different behavioral effects of clinical vs non-clinical paclitaxel formulations in preclinical models of peripheral neuropathy. The results indicate a need to consider specific formulations for peripheral neuropathy models and suggest a potential to choose new paclitaxel derivatives with neuropathic effects of lesser severity and duration. The results also highlight the challenges faced in translating results obtained in preclinical models to the design of new formulations for human treatments.