Drug Interaction Report

MONITOR: Coadministration with sotorasib may decrease the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The proposed mechanism is increased metabolic clearance due to induction of CYP450 3A4 by sotorasib. When midazolam, a sensitive CYP450 3A4 substrate, was coadministered with sotorasib, midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 48% and 53%, respectively. These results suggest moderate induction of CYP450 3A4 by sotorasib.

MANAGEMENT: Caution is advised when sotorasib is used concomitantly with drugs that are substrates of CYP450 3A4, particularly sensitive substrates or those with a narrow therapeutic range. The prescribing information recommends avoiding coadministration of sotorasib with CYP450 3A4 substrates for which minimal concentration changes may lead to therapeutic failure. If coadministration is required, dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever sotorasib is added to or withdrawn from therapy. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration of a moderate CYP450 3A4 inducer like sotorasib and for any dosage adjustments that may be required.

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.

Food does not appear to have a clinically significant effect on the oral bioavailability of sotorasib. When a 960 mg dose of sotorasib was administered to study patients with a high-fat, high-calorie meal (approximately 800 to 1000 calories; 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively), sotorasib peak plasma concentration (Cmax) did not change while systemic exposure (AUC 0-24 hours) increased by 25% compared to administration under fasted conditions. Sotorasib can be administered with or without food at approximately the same time each day.