Drug Interaction Report

Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of atogepant, which is primarily metabolized by the isoenzyme. When atogepant was administered with the potent CYP450 3A4 inhibitor itraconazole in healthy study subjects, atogepant peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 2.2- and 5.5-fold, respectively. However, moderate and weak inhibitors may interact to a much lesser extent. Population pharmacokinetic modeling has suggested that moderate (e.g., cyclosporine, ciprofloxacin, fluconazole, fluvoxamine, grapefruit juice) or weak (e.g., cimetidine, esomeprazole) CYP450 3A4 inhibitors may increase atogepant AUC by 1.7- and 1.1-fold, respectively. The changes in atogepant exposure when coadministered with moderate or weak CYP450 3A4 inhibitors are not expected to be clinically significant.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of nilotinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Because nilotinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of nilotinib. The mechanism of interaction is unknown. Compared to the fast state, nilotinib systemic exposure (AUC) increased by 82% when the dose was given 30 minutes after a high-fat meal. Because nilotinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

MANAGEMENT: Patients treated with nilotinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. In addition, no food should be consumed for at least 2 hours before and 1 hour after a nilotinib dose.