Drug Interaction Report

MONITOR: Coadministration with tucatinib may increase the plasma concentrations of CYP450 3A4 substrates. The mechanism involves tucatinib-mediated inhibition of CYP450 3A isoenzymes. When a single 2 mg dose of midazolam, a CYP450 3A substrate, was administered with tucatinib (300 mg twice daily), midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 3-fold and 5.7-fold, respectively. Increased exposure to the CYP450 3A substrate may increase the risk of toxicity.

MANAGEMENT: Caution is advised when tucatinib is used concomitantly with drugs that undergo metabolism by CYP450 3A4. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever tucatinib is added to or withdrawn from therapy.

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.