Model-informed drug repurposing of proton pump inhibitors for the prevention of oxaliplatin induced peripheral neuropathy: A real-world data analysis and pharmacometrics approach.

Abstract

Purpose: Oxaliplatin (L-OHP) is a platinum-based anticancer agent that induces peripheral neuropathy (OIPN), a dose-limiting toxicity caused by platinum accumulation in the dorsal root ganglion (DRG) and neuronal damage. Proton pump inhibitors (PPIs) have recently been proposed as preventive agents for OIPN; however, they have not been clinically implemented. This study aimed to evaluate the ameliorative effects of PPIs on OIPN using real-world data and a pharmacometrics approach based on animal data.

Methods: Real-world database analysis was conducted using the Japanese Adverse Drug Event Report (JADER) database. We calculated the reporting odds ratios to evaluate the effects of the candidate drugs. Rats were intravenously administered L-OHP (5 mg/kg) once a week. Omeprazole (2-20 mg/kg) or esomeprazole (1-10 mg/kg) was orally administered on the five times a week. Blood and DRG samples were collected after L-OHP administration. The OIPN was assessed using the von Frey test. A pharmacokinetic-toxicodynamic (PK-TD) model analysis was performed using the obtained data.

Results: The JADER analysis suggested that omeprazole may have a suppressive effect on OIPN. In animal study, co-administration of omeprazole or esomeprazole significantly decreased the platinum concentration in the DRG compared with L-OHP monotherapy and suppressed the development of OIPN in a dose-dependent manner. The PK-TD model of platinum composed of the DRG compartment quantitatively described the preventive effects of omeprazole and esomeprazole on OIPN.

Conclusion: Omeprazole and esomeprazole may be valuable agents for suppressing OIPN by inhibiting platinum influx into the DRG and exerting a potential neuroprotective effect.