Drug Interaction Report

MONITOR: Coadministration with lenacapavir may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. According to the manufacturer, lenacapavir is a moderate inhibitor of CYP450 3A4 and due to its long half-life after subcutaneous administration, it may increase the exposure to and risk of adverse reactions to drugs primarily metabolized by CYP450 3A4 that are initiated within 9 months after the last subcutaneous lenacapavir dose. In pharmacokinetic studies in fed subjects without HIV, coadministration of oral lenacapavir (600 mg twice daily for 2 days, then a single 600 mg dose) with the sensitive CYP450 3A4 substrate midazolam (single 2.5 mg dose orally at the same time as the single lenacapavir dose) led to an increase in midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.9-fold and 3.6-fold, respectively.

MANAGEMENT: Caution is advised if lenacapavir is coadministered with drugs that are substrates of CYP450 3A4, particularly sensitive substrates or those with a narrow therapeutic index. Due to its long half-life, the effect may persist for up to 9 months after the last subcutaneous dose, so caution and monitoring for adverse effects are also advised during this time. The prescribing information for the coadministered drug should also be consulted for specific dosing recommendations.

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.