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: Coadministration with grapefruit juice may increase the plasma concentrations of eplerenone. The primary mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Inhibition of hepatic CYP450 3A4 may also contribute. In drug interaction studies, administration of a single 100 mg dose of eplerenone in combination with grapefruit juice resulted in a 25% increase in eplerenone systemic exposure (AUC). High blood levels of eplerenone can increase the risk of side effects including hyperkalemia. 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.

MANAGEMENT: It may be advisable for patients to avoid the consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with eplerenone.