sdz-psc-833 and Peripheral-Nervous-System-Diseases

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. Patients with cancer 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 while a 4.7-fold (95% CI 1.9-11.9) increased risk for patients treated with strong P-gp inhibitors was observed, 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 comedication with P-gp inhibitors may lead to increased risk of PIPN.

Topics: Antineoplastic Agents, Phytogenic; Atorvastatin; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Cyclosporins; Dose-Response Relationship, Drug; Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Neurons; Paclitaxel; Peripheral Nervous System Diseases; Retrospective Studies; Risk Assessment; Risk Factors; Simvastatin; Verapamil