Drug Interaction Report

MONITOR: Coadministration of fostamatinib with inhibitors of CYP450 3A4 may increase exposure to the active metabolite known as R406, the predominant moiety in the systemic circulation following fostamatinib administration. Fostamatinib is metabolized in the gut by alkaline phosphatase to R406, which then undergoes oxidation via CYP450 3A4 and glucuronidation via UGT1A9. In vitro, R406 is also a substrate of the P-glycoprotein (P-gp) efflux transporter. When a single 80 mg dose of fostamatinib (0.53 times the 150 mg dosage) was administered with the potent CYP450 3A4 inhibitor ketoconazole (200 mg twice daily for 3.5 days), R406 peak plasma concentration (Cmax) and systemic exposure (AUC) increased on average by 37% and 102%, respectively, compared to fostamatinib administered alone. When a single 150 mg dose of fostamatinib was administered with the moderate CYP450 3A4 inhibitor verapamil (80 mg three times daily for 4 days), R406 Cmax and AUC increased on average by 6% and 39%, respectively. Increased exposure to R406 may result in increased risk of adverse effects such as diarrhea, hepatotoxicity, hypertension, and neutropenia. Both ketoconazole and verapamil are also significant inhibitors of P-gp, although the extent to which P-gp inhibition may contribute to the interaction is unknown.

MANAGEMENT: Patients should be monitored for toxicities of fostamatinib during concomitant use of potent or moderate CYP450 3A4 inhibitors or dual CYP450 3A4/P-gp inhibitors, and the fostamatinib dosage adjusted as necessary in accordance with the product labeling.

GENERALLY AVOID: Grapefruit and/or grapefruit juice may increase the systemic exposure to palbociclib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Increased exposure to palbociclib may increase the risk of adverse effects such as infections, neutropenia, leukopenia, anemia, thrombocytopenia, anorexia, nausea, vomiting, diarrhea, stomatitis, alopecia, asthenia, peripheral neuropathy, and epistaxis.

ADJUST DOSING INTERVAL: Food may enhance the oral bioavailability of palbociclib capsules and reduce the intersubject variability of palbociclib exposure. According to the product labeling, absorption and exposure of palbociclib from its oral capsule formulation were very low in approximately 13% of the population when taken in the fasted state. Food intake increased the palbociclib exposure in this small subset of the population but did not alter exposure in the rest of the population to a clinically relevant extent. Compared to palbociclib capsules given under overnight fasted conditions, the population average palbociclib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 38% and 21%, respectively, when given with high-fat, high-calorie food (approximately 800 to 1000 calories; 150, 250, and 500 to 600 calories from protein, carbohydrate and fat, respectively); by 27% and 12%, respectively, when given with low-fat, low-calorie food (approximately 400 to 500 calories; 120, 250, and 28 to 35 calories from protein, carbohydrate and fat, respectively); and by 24% and 13%, respectively, when given with moderate-fat, standard calorie food (approximately 500 to 700 calories; 75 to 105, 250 to 350 and 175 to 245 calories from protein, carbohydrate and fat, respectively) one hour before and two hours after palbociclib capsule dosing.

MANAGEMENT: Patients should avoid consumption of grapefruit or grapefruit juice while on treatment with palbociclib. To avoid variability in drug absorption between doses, palbociclib capsules should be taken with food. Palbociclib tablet formulations may be taken with or without food.