Drug Interaction Report

GENERALLY AVOID: Coadministration with inhibitors of UGT1A1 may increase the plasma concentrations of belinostat, which is primarily (80% to 90%) metabolized by UGT1A1-mediated glucuronidation. Atazanavir, a UGT1A1 inhibitor, decreased the peak plasma concentration (Cmax) of belinostat by 33% but increased systemic exposure (AUC) by 1.4-fold.

MANAGEMENT: Concomitant use of belinostat with UGT1A1 inhibitors should generally be avoided. If concomitant use of a UGT1A1 inhibitor is unavoidable, the manufacturer recommends that the dosage of belinostat be decreased by 25%; 1,000 mg/m2 dose modified to 750 mg/m2, 750 mg/m2 dose modified to 562.5 mg/m2, and 500 mg/m2 dose discontinued for the duration of UGT1A1 inhibitor use and restarted at the previous dose after five half-lives of the UGT1A1 inhibitor. Patients should be monitored closely for potentially increased adverse effects of belinostat such as nausea, vomiting, diarrhea, thrombocytopenia, leukopenia (neutropenia and lymphopenia), anemia, infection, and hepatotoxicity.

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.