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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever tucatinib is added to or withdrawn from therapy.

MONITOR: Coadministration with tucatinib may increase the plasma concentrations of drugs that are substrates of the P-glycoprotein (P-gp) transporter. The mechanism likely involves tucatinib-mediated inhibition of P-gp. When a single 0.5 mg dose of digoxin, a P-gp substrate, was administered with tucatinib (300 mg twice daily), digoxin peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2.4-fold and 1.5-fold, respectively. Increased exposure to the P-gp substrate may increase the risk of toxicity.

MANAGEMENT: Caution is advised if tucatinib is used concomitantly with P-gp substrates, particularly those with a narrow therapeutic index. A dose reduction of the P-gp substrates as well as clinical and laboratory monitoring may be appropriate.

Food enhances the oral absorption and bioavailability of tenofovir, the active entity of tenofovir disoproxil fumarate. According to the product labeling, administration of the drug following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of tenofovir by approximately 14% and 40%, respectively, compared to administration in the fasting state. However, administration with a light meal did not significantly affect the pharmacokinetics of tenofovir compared to administration in the fasting state. Food delays the time to reach tenofovir Cmax by approximately 1 hour. Tenofovir disoproxil fumarate may be administered without regard to meals.