Drug Interaction Report

MONITOR: Coadministration with daclatasvir may increase the plasma concentrations of drugs that are substrates of the P-glycoprotein (P-gp) transporter. The proposed mechanism is decreased clearance in the intestine, liver, and/or kidney due to inhibition of P-glycoprotein-mediated drug efflux by daclatasvir. When 0.125 mg once daily of digoxin, a P-gp probe substrate, was administered with 60 mg once daily daclatasvir, digoxin peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 65% and 27%, respectively.

MANAGEMENT: Caution is advised when daclatasvir is used concurrently with drugs that are known P-gp substrates, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever daclatasvir is added to or withdrawn from therapy.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of lapatinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

ADJUST DOSING INTERVAL: Food can significantly increase the oral bioavailability of lapatinib. According to the manufacturer, lapatinib peak plasma concentration (Cmax) was approximately 2.5- and 3-fold higher and systemic exposure (AUC) 3- and 4-fold higher when administered with a low fat meal (5% fat; 500 calories) or with a high-fat meal (50% fat; 1000 calories), respectively, compared to fasting. Dividing the daily dose also resulted in an approximately 2-fold higher systemic exposure at steady state compared to the same total dose administered once daily.

MANAGEMENT: Patients treated with lapatinib should preferably avoid the consumption of grapefruit or grapefruit juice. The manufacturer recommends that lapatinib be administered at least one hour before or one hour after a meal. The lapatinib dose is administered once daily and should not be divided.