Drug Interactions between capivasertib and revumenib

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of capivasertib, which is primarily metabolized by CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice but has been studied with other CYP450 3A4 inhibitors. Based on clinical studies and model-informed approaches, concomitant use with the potent CYP450 3A4 inhibitor itraconazole is predicted to increase capivasertib systemic exposure (AUC) by up to 1.7-fold and peak plasma concentration (Cmax) by up to 1.4-fold. Coadministration with the moderate CYP450 3A4 inhibitors erythromycin and verapamil is predicted to increase the AUC and Cmax of capivasertib by up to 1.5-fold 1.3-fold, respectively. 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. Increased exposure to capivasertib may increase the risk of adverse effects such as diarrhea, cutaneous adverse reactions, decreased lymphocytes, decreased hemoglobin, hyperglycemia, nausea, and fatigue.

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

ADJUST DOSING INTERVAL: In pharmacokinetic studies, revumenib was administered while fasting or with a low fat meal. Revumenib has not been studied with meals of higher fat content and the impact on its pharmacokinetic parameters is unknown.

MONITOR: Grapefruit, grapefruit juice, grapefruit hybrids, pomelos, star-fruit, and Seville oranges may increase the plasma concentrations of revumenib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The extent and clinical significance are unknown. In pharmacokinetic studies in patients with relapsed or refractory acute leukemia, revumenib area under the concentration-time curve (AUC) and peak plasma concentration (Cmax) increased 2-fold following concomitant use with the potent CYP450 3A4 inhibitors posaconazole, itraconazole, and voriconazole, and 2.5-fold following concomitant use with the potent CYP450 3A4 inhibitor cobicistat. However, clinically significant differences in revumenib pharmacokinetics were not observed when used concomitantly with the moderate CYP450 3A4 inhibitors fluconazole and isavuconazole. 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. Moreover, pharmacokinetic alterations associated with interactions involving grapefruit juice are often subject to a high degree of interpatient variability. Increased exposure to revumenib may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death.

MANAGEMENT: Due to the potential impact of high fat content meals on revumenib absorption and exposure, it is recommended that revumenib be administered while fasting or with a low fat meal (approximately 400-500 calories, with 25% of calories from fat). In addition, if grapefruit, grapefruit juice, grapefruit hybrids, pomelos, star-fruit, or Seville oranges are consumed during treatment with revumenib, assess patient tolerability and monitor for serious adverse effects (e.g., QT prolongation and torsade de pointes arrhythmia, differentiation syndrome, neutropenia, thrombocytopenia).