Drug Interactions between brigatinib and mefloquine

ADJUST DOSING INTERVAL: Food enhances the oral absorption and bioavailability of mefloquine. The proposed mechanism is increased drug solubility in the presence of food. In 20 healthy volunteers, administration of a single 750 mg oral dose of mefloquine 30 minutes following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of mefloquine by 73% and 40%, respectively, compared to administration in the fasting state. The Cmax and AUC of the carboxylic acid metabolite were also increased by 35% and 33%, respectively, compared to fasting. In addition, the time to reach peak plasma concentration (Tmax) of mefloquine was significantly shorter after food intake (17 hours) than in the fasting state (36 hours). There was no difference in the elimination half-life of mefloquine and metabolite, or the Tmax for the metabolite.

MANAGEMENT: To ensure maximal oral absorption, mefloquine should be administered immediately after a meal with at least 8 ounces of water.

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.