Drug Interactions between lapatinib and pemigatinib

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of pemigatinib, which is primarily metabolized by CYP450 3A4 in vitro. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice but has been reported for other CYP450 3A4 inhibitors. When itraconazole, a potent CYP450 3A4 inhibitor, was administered following a single oral pemigatinib dose of 4.5 mg, pemigatinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 17% and 88%, respectively. Concomitant use of moderate CYP450 3A4 inhibitors is predicted to increase pemigatinib exposure by approximately 50% to 80%. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to pemigatinib may increase the incidence and severity of serious adverse reactions such as hyperphosphatemia (which can cause precipitation of calcium-phosphate crystals over time that can lead to hypocalcemia, soft tissue mineralization such as cutaneous calcification and calcinosis, secondary hyperparathyroidism, anemia, muscle cramps, seizures, QT prolongation, and arrhythmias), serous retinal detachment (which may cause symptoms such as blurred vision, visual floaters, or photopsia), palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), arthralgia, stomatitis, diarrhea, nausea, vomiting, and constipation.

Pemigatinib pharmacokinetics were not significantly affected by coadministration of a high-fat, high-calorie meal (approximately 1000 calories; 500 to 600 calories from fat).

MANAGEMENT: Pemigatinib may be administered with or without food. Patients should avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit extract during treatment with pemigatinib.

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.