Drug Interactions between encorafenib and ibrexafungerp

GENERALLY AVOID: Coadministration with potent or moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of encorafenib, which is primarily metabolized by the isoenzyme. When a single 50 mg dose of encorafenib (equivalent to 0.1 times the recommended dose) was administered with posaconazole, a potent CYP450 3A4 inhibitor, encorafenib peak plasma concentration (Cmax) increased by 68% and systemic exposure (AUC) increased by 3-fold. When the same dose of encorafenib was administered with diltiazem, a moderate CYP450 3A4 inhibitor, encorafenib Cmax increased by 45% and AUC increased by 2-fold. Increased exposure to encorafenib may increase the risk of serious and life-threatening adverse effects such as hemorrhage, uveitis, QT prolongation, hepatotoxicity, dermatologic reactions, and new malignancies.

MANAGEMENT: Concomitant use of encorafenib with grapefruit or grapefruit juice should generally be avoided. If coadministration is required, the manufacturer recommends reducing the encorafenib dose to one-third of the dose used prior to addition of a potent CYP450 3A4 inhibitor or one-half of the dose used prior to addition of a moderate CYP450 3A4 inhibitor. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, the encorafenib dose that was taken prior to initiating the inhibitor may be resumed.

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of ibrexafungerp. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. 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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. In healthy subjects receiving the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily for 15 days), ibrexafungerp peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2.5-fold and 5.8-fold, respectively. Increased plasma concentrations of ibrexafungerp may increase the risk for adverse effects such as diarrhea, nausea, abdominal pain, dizziness, and vomiting.

When administered to healthy volunteers with a high-fat meal (800 to 1000 calories; 50% fat), ibrexafungerp Cmax and AUC increased 32% and 38%, respectively, compared to fasted conditions.

MANAGEMENT: Ibrexafungerp may be administered with or without food. However, avoiding consumption of grapefruit or grapefruit juice during treatment with ibrexafungerp may be advisable.