Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of unconjugated monomethyl auristatin E (MMAE), the anti-mitotic and cytotoxic component of telisotuzumab vedotin. Telisotuzumab vedotin is an antibody-drug conjugate (ADC) that releases MMAE via proteolytic cleavage, and MMAE has been shown in vitro to be primarily metabolized by CYP450 3A4. MMAE systemic exposure (AUC) is predicted to increase by 1.4-fold following concomitant administration of telisotuzumab vedotin with the potent CYP450 3A4 inhibitor ketoconazole. It is not known if, and to what extent, MMAE may interact with less potent CYP450 3A4 inhibitors.

MANAGEMENT: Caution is advised when telisotuzumab vedotin is used concomitantly with CYP450 3A4 inhibitors. Patients should be closely monitored for development or exacerbation of toxicities such as ocular surface disorders (e.g., dry eyes, keratitis, blurred vision), peripheral neuropathy, interstitial lung disease/pneumonitis, and peripheral edema. If serious adverse reactions occur, the dosing of telisotuzumab vedotin should be adjusted or withheld as necessary in accordance with the product labeling.

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.