Drug Interaction Report

GENERALLY AVOID: Coadministration with moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of mobocertinib, which is primarily metabolized by the isoenzyme. Elevated plasma concentrations of mobocertinib may increase the risk for adverse effects such as QT prolongation, heart failure or reduced ejection fraction, cardiomyopathy, heart block, diarrhea, rash, stomatitis, fatigue, and musculoskeletal pain. The risk of QT prolongation in particular may be increased with concomitant use of moderate CYP450 3A4 inhibitors that are also known to prolong the QT interval (e.g., ciprofloxacin, crizotinib, dronedarone, erythromycin, fluconazole, ribociclib). Based on drug interaction studies using model-informed approaches, coadministration of mobocertinib with repeated doses of a moderate CYP450 3A4 inhibitor is predicted to increase the steady-state combined molar AUC (systemic exposure) of mobocertinib and its active metabolites by approximately 100% to 200%.

MANAGEMENT: Concomitant use of mobocertinib with moderate CYP450 3A4 inhibitors should be avoided when possible. If coadministration is required, the dosage of mobocertinib should be reduced by approximately 50% (from 160 mg to 80 mg, 120 mg to 40 mg, or 80 mg to 40 mg) and the QTc interval monitored more frequently with electrocardiograms, especially in patients treated with moderate CYP450 3A4 inhibitors that are also known to prolong the QT interval. Mobocertinib may be resumed at the previous dose after the moderate CYP450 3A4 inhibitor has been discontinued for 3 to 5 elimination half-lives.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of mobocertinib. The mechanism may involve inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice. Based on drug interaction studies using model-informed approaches, coadministration of mobocertinib with multiple doses of itraconazole or ketoconazole (strong CYP450 3A4 inhibitors) is predicted to increase the steady-state combined molar AUC (systemic exposure) of mobocertinib and its active metabolites by 374% to 419%, while coadministration with multiple doses of a moderate CYP450 3A4 inhibitor is predicted to increase this value by approximately 100% to 200%. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Elevated plasma concentrations of mobocertinib may increase the risk for adverse effects such as QT prolongation, heart failure or reduced ejection fraction, cardiomyopathy, heart block, diarrhea, rash, stomatitis, fatigue, and musculoskeletal pain.

MANAGEMENT: Patients should avoid consumption of grapefruit and grapefruit juice during treatment with mobocertinib.

ADJUST DOSING INTERVAL: Food enhances the absorption and oral bioavailability of darunavir administered in combination with low-dose ritonavir. The mechanism is unknown. When administered with food, the peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of darunavir were approximately 30% higher than when administered in the fasting state. Darunavir exposure was similar for the range of meals studied. The total caloric content of the various meals evaluated ranged from 240 Kcal (12 grams fat) to 928 Kcal (56 grams fat).

MANAGEMENT: To ensure maximal oral absorption, darunavir coadministered with ritonavir should be taken with food. The type of food is not important.