Drug Interactions between nilotinib and sodium zirconium cyclosilicate

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of nilotinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Because nilotinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of nilotinib. The mechanism of interaction is unknown. Compared to the fast state, nilotinib systemic exposure (AUC) increased by 82% when the dose was given 30 minutes after a high-fat meal. Because nilotinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

MANAGEMENT: Patients treated with nilotinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. In addition, no food should be consumed for at least 2 hours before and 1 hour after a nilotinib dose.

ADJUST DOSING INTERVAL: Because sodium zirconium cyclosilicate can transiently increase gastric pH, it may affect the absorption of coadministered medications that exhibit pH-dependent solubility. Altered efficacy or safety of these medications may occur when they are administered too close to the dosing of sodium zirconium cyclosilicate. According to the product labeling, 39 drugs were tested to determine potential interactions with sodium zirconium cyclosilicate. Drugs that did not show an in vitro interaction with sodium zirconium cyclosilicate were allopurinol, apixaban, aspirin, captopril, cyclosporine, digoxin, ethyl estradiol, lisinopril, magnesium, metformin, phenytoin, prednisone, propranolol, quinapril, spironolactone, and ticagrelor. Of the 23 drugs that showed an in vitro interaction, nine were subsequently tested in healthy volunteers. Losartan, glipizide, and levothyroxine did not demonstrate an in vivo interaction with sodium zirconium cyclosilicate. However, an increase in systemic exposure was observed for weak acids such as furosemide and atorvastatin when coadministered with sodium zirconium cyclosilicate, while a decrease in systemic exposure was observed for weak bases such as dabigatran.

MANAGEMENT: In general, concomitant oral medications should be administered at least 2 hours before or 2 hours after sodium zirconium cyclosilicate. Separation of dosing times is not needed if it has been determined that the concomitant medication does not exhibit pH-dependent solubility.