Drug Interactions between larotrectinib and vadadustat

Consumer information for this interaction is not currently available.

MONITOR: Coadministration with inhibitors of CYP450 3A4, P-glycoprotein (P-gp), and/or breast cancer resistance protein (BCRP) may increase the plasma concentrations of larotrectinib. According to the prescribing information, larotrectinib is metabolized primarily by the CYP450 3A4 isoenzyme and is a substrate of the P-gp and BCRP efflux transporters in vitro. When a single 100 mg dose of larotrectinib was coadministered with itraconazole (200 mg once daily for 7 days), a potent CYP450 3A4 inhibitor and P-gp/BCRP inhibitor, larotrectinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2.8- and 4.3-fold, respectively, compared to administration of larotrectinib alone. When a single 100 mg dose of larotrectinib was administered in healthy adult subjects with a single 600 mg dose of rifampin (a P-gp and BCRP inhibitor during initial use, but an inducer of CYP450 3A4 and P-gp following chronic use), larotrectinib Cmax and AUC increased by 1.8- and 1.7-fold, respectively. Coadministration with fluconazole, a moderate CYP450 3A4 inhibitor, is predicted to increase larotrectinib steady-state Cmax by 1.9-fold and AUC by 2.7-fold.

MANAGEMENT: Caution is advised when larotrectinib is used with CYP450 3A4, P-gp, and/or BCRP inhibitors. Patients should be monitored more frequently for adverse effects such as neurotoxicity (delirium, dysarthria, dizziness, gait disturbance, paraesthesia, encephalopathy, memory impairment, tremor) and hepatotoxicity (elevations in liver transaminases), and the larotrectinib dosage adjusted based on severity of emergent adverse reactions in accordance with the product labeling.