Drug Interactions between Abraxane and omaveloxolone

MONITOR: Coadministration with inhibitors of CYP450 3A4, such as grapefruit juice, may increase the plasma concentrations of paclitaxel, which is a substrate of the isoenzyme. Current data suggest that consumption of large quantities of grapefruit juice inhibit both intestinal and hepatic CYP450 3A4 due to certain compounds present in grapefruit. Specific data for paclitaxel are lacking; however, in a case report of a 52-year-old woman with esophageal squamous cell carcinoma receiving a twice weekly chemotherapy regimen including intravenous docetaxel (40 mg/m2) reported that docetaxel systemic exposure (AUC) increased by 65% compared with the AUC target of 1.96 mg*h/L and clearance decreased by 63%, with a 71% reduction in the patient's neutrophil count. In the absence of other CYP450 3A4 inhibitors, these effects were attributed to daily consumption of 250 mL of grapefruit juice, which the patient had been consuming for at least 3 months. Two weeks after the patient ceased the grapefruit juice, the docetaxel AUC was closer to the target value and the neutrophil count reduction was less than 35%. In addition, in a pharmacokinetic study consisting of 7 cancer patients, mean dose-normalized docetaxel AUC increased by 2.2-fold and clearance decreased by 49% when intravenous docetaxel was given at a reduced dosage of 10 mg/m2 in combination with the potent CYP450 3A4 inhibitor ketoconazole (200 mg orally once daily for 3 days) compared to docetaxel administered alone at 100 mg/m2.

MANAGEMENT: Caution is recommended if paclitaxel is to be used in combination with grapefruit and grapefruit juice. Patients should be closely monitored for the development of paclitaxel toxicity, including diarrhea, mucositis, myelosuppression, and peripheral neuropathy and dose adjustment considered per local treatment protocols.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of omaveloxolone, 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 reported for other CYP450 3A4 inhibitors. When administered with itraconazole, a potent CYP450 3A4 inhibitor, omaveloxolone peak plasma concentration (Cmax) and systemic exposure (AUC) increased 3-fold and 4-fold, respectively. When administered with verapamil, a moderate CYP450 3A4 inhibitor, omaveloxolone Cmax and AUC increased approximately 1.25-fold each. 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 omaveloxolone may increase the risk of adverse reactions such as lipid abnormalities and increased aminotransferases and B-type natriuretic peptide (BNP).

ADJUST DOSING INTERVAL: Food may increase the oral bioavailability of omaveloxolone. Coadministration with a high-fat meal (800 to 1000 calories, with approximately 150, 250, and 500 to 600 calories from protein, carbohydrates, and fat, respectively) increased omaveloxolone Cmax and AUC by approximately 350% and 15%, respectively, compared to fasted conditions.

MANAGEMENT: Omaveloxolone should be administered on an empty stomach at least 1 hour before eating. Patients should avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with omaveloxolone.