Drug Interactions between capivasertib and encorafenib

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: 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.

The recommended maximum number of medicines in the 'multikinase inhibitors' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'multikinase inhibitors' category:

• capivasertib
• encorafenib

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.