P‐Glycoprotein Inhibition Exacerbates Paclitaxel Neurotoxicity in Neurons and Patients With Cancer

Abstract

Paclitaxel‐induced peripheral neuropathy (PIPN) is a common and dose‐limiting adverse event. The role of P‐glycoprotein (P‐gp) in the neuronal efflux of paclitaxel was assessed using a translational approach. SH‐SY5Y cells were differentiated to neurons and paclitaxel toxicity in the absence and presence of a P‐gp inhibitor was determined. Paclitaxel caused marked dose‐dependent toxicity in SH‐SY5Y‐derived neurons. Paclitaxel neurotoxicity was exacerbated with concomitant P‐gp inhibition by valspodar and verapamil, consistent with increased intracellular accumulation of paclitaxel. Cancer patients treated with paclitaxel and P‐gp inhibitors had a 2.4‐fold (95% confidence interval (CI): 1.3‐4.3) increased risk of peripheral neuropathy‐induced dose modification, a 4.7‐fold (95% CI: 1.9‐11.9) increased risk for patients treated with strong P‐gp inhibitors and a 7.0‐fold (95% CI: 2.3‐21.5) increased risk in patients treated with atorvastatin. Atorvastatin also increased neurotoxicity by paclitaxel in SH‐SY5Y‐derived neurons. Clinicians should be aware that co‐medication with P‐gp inhibitors may lead to increased risk of PIPN.