Drug Interaction Report

MONITOR: Coadministration with inhibitors of P-glycoprotein (P-gp) may increase the plasma concentrations of mitoxantrone, which is a substrate of the efflux transporter also known as ABCB1 or MDR1. The interaction has been studied with cyclosporine, a potent P-gp inhibitor. In a pharmacokinetic study of 38 children with de novo acute myeloid leukemia, mitoxantrone 6 mg/m2 administered daily in combination with cyclosporine resulted in a 42% decrease in mean mitoxantrone clearance and 12% increase in systemic exposure (AUC) compared to mitoxantrone 10 mg/m2 administered daily without cyclosporine. There were no differences in the rates of stomatitis or infection between the two groups, but an increased incidence of hyperbilirubinemia was observed in the cyclosporine group, which rapidly reversed upon conclusion of treatment. Therefore, it appears a 40% dose reduction of mitoxantrone given with cyclosporine produced statistically similar systemic exposure and toxicity as mitoxantrone given alone.

MANAGEMENT: Caution is advised if mitoxantrone is prescribed in combination with a P-gp inhibitor. Patients should be closely monitored for increased adverse effects including cardiotoxicity and myelosuppression.

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.