Drug Interactions between brigatinib and Di-Phen

ADJUST DOSING INTERVAL: Phenytoin bioavailability may decrease to subtherapeutic levels when the suspension is given concomitantly with enteral feedings. The mechanism may be related to phenytoin binding to substances in the enteral formula (e.g., calcium, protein) and/or binding to the tube lumen. Data have been conflicting and some studies have reported no changes in phenytoin levels, while others have reported significant reductions.

MONITOR: Acute consumption of alcohol may increase plasma phenytoin levels. Chronic consumption of alcohol may decrease plasma phenytoin levels. The mechanism of this interaction is related to induction of phenytoin metabolism by ethanol during chronic administration. Other hydantoin derivatives may be similarly affected by ethanol.

MANAGEMENT: Some experts have recommended interrupting the feeding for 2 hours before and after the phenytoin dose, giving the phenytoin suspension diluted in water, and flushing the tube with water after administration; however, this method may not entirely avoid the interaction and is not always clinically feasible. Patients should be closely monitored for clinical and laboratory evidence of altered phenytoin efficacy and levels upon initiation and discontinuation of enteral feedings. Dosage adjustments or intravenous administration may be required until therapeutic serum levels are obtained. In addition, patients receiving phenytoin therapy should be warned about the interaction between phenytoin and ethanol and they should be advised to notify their physician if they experience worsening of seizure control or symptoms of toxicity, including drowsiness, visual disturbances, change in mental status, nausea, or ataxia.

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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.

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