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 lapatinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

ADJUST DOSING INTERVAL: Food can significantly increase the oral bioavailability of lapatinib. According to the manufacturer, lapatinib peak plasma concentration (Cmax) was approximately 2.5- and 3-fold higher and systemic exposure (AUC) 3- and 4-fold higher when administered with a low fat meal (5% fat; 500 calories) or with a high-fat meal (50% fat; 1000 calories), respectively, compared to fasting. Dividing the daily dose also resulted in an approximately 2-fold higher systemic exposure at steady state compared to the same total dose administered once daily.

MANAGEMENT: Patients treated with lapatinib should preferably avoid the consumption of grapefruit or grapefruit juice. The manufacturer recommends that lapatinib be administered at least one hour before or one hour after a meal. The lapatinib dose is administered once daily and should not be divided.