Drug Interaction Report

MONITOR: Coadministration with brigatinib may increase the plasma concentrations and risk of adverse effects of drugs that are substrates of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic cation transporter 1 (OCT1), and/or multidrug and toxin extrusion protein 1 (MATE1), and 2K (MATE2K). The proposed mechanism, based on in vitro data, is decreased drug clearance due to brigatinib-mediated inhibition of these transport proteins.

MANAGEMENT: Caution is advised if brigatinib is used concomitantly with drugs that are substrates of P-gp, BCRP, OCT 1, MATE 1, and/or MATE 2K transport proteins, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring should be considered whenever brigatinib is added to or withdrawn from therapy with these drugs. Patients should be monitored for the development of adverse effects.

ADJUST DOSING INTERVAL: Food may reduce as well as delay the absorption of trametinib. In study subjects, administration of a single dose of trametinib with a high-fat, high-calorie meal decreased peak plasma concentration (Cmax) and systemic exposure (AUC) by 70% and 24%, respectively, and delayed Tmax by approximately 4 hours compared to administration in the fasted state.

MANAGEMENT: Trametinib should be taken at least 1 hour before or 2 hours after a meal.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of brigatinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. 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. Itraconazole, a potent CYP450 3A4 inhibitor, has been shown to double brigatinib systemic exposure (AUC) in healthy volunteers. Increased exposure to brigatinib may increase the risk of adverse effects such as nausea, vomiting, diarrhea, hypertension, bradycardia, hyperglycemia, visual disturbances, lymphopenia, anemia, and elevations in pancreatic enzymes and creatine phosphokinase.

Food does not significantly affect the oral bioavailability of brigatinib. When brigatinib was administered to healthy volunteers after a high-fat meal (920 calories; 59 g fat, 58 g carbohydrates, 40 g proteins), brigatinib peak plasma concentration (Cmax) decreased by 13% and systemic exposure (AUC) did not change compared to administration after overnight fasting.

MANAGEMENT: Brigatinib may be taken with or without food. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with brigatinib.

The recommended maximum number of medicines in the 'multikinase inhibitors' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'multikinase inhibitors' category:

• brigatinib
• trametinib

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.