Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of lapatinib, which is primarily metabolized by the isoenzyme. In healthy subjects, administration of lapatinib in combination with the CYP450 3A4 inhibitor ketoconazole (200 mg twice daily for 7 days) resulted in lapatinib systemic exposure (AUC) and half-life that were approximately 3.6- and 1.7-fold, respectively, of the control values.

MANAGEMENT: Concomitant use of lapatinib with potent CYP450 3A4 inhibitors should generally be avoided. Some authorities recommend avoiding concomitant use of lapatinib during and for 2 weeks after treatment with itraconazole. If coadministration is required, the manufacturer recommends reducing the lapatinib dosage to 500 mg once a day. Based on pharmacokinetic studies, this dosage is predicted to adjust the lapatinib systemic exposure (AUC) to the range observed without inhibitors. However, clinical data are lacking. Following discontinuation of the potent CYP450 3A4 inhibitor, a washout period of approximately one week should be allowed before the lapatinib dosage is adjusted upward to the indicated dosage (i.e., 1250 mg once a day).

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.