Drug Interactions between abemaciclib and bedaquiline

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of bedaquiline. When administered with a standard meal containing approximately 22 grams of fat (558 total Kcal), the relative bioavailability of bedaquiline increased by approximately 2-fold compared to administration under fasted conditions.

GENERALLY AVOID: Coadministration with alcohol may increase the risk of hepatotoxicity associated with the use of bedaquiline. In clinical trials, hepatic adverse drug reactions developed in more bedaquiline-treated patients than in those who received other drugs used to treat tuberculosis. In patients receiving bedaquiline or placebo in combination with other drugs used to treat multidrug-resistant tuberculosis, reversible aminotransferase elevations of at least 3 times the upper limit of normal developed more frequently in the bedaquiline treatment group [10.8%] than in the placebo group [5.7%].

MANAGEMENT: To ensure maximal oral absorption, bedaquiline should be taken with food. Patients should avoid alcohol use during treatment.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of abemaciclib. 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. According to the product labeling, abemaciclib systemic exposure (AUC) is predicted to increase by up to 16-fold when administered with the potent CYP450 3A4 inhibitor ketoconazole. Itraconazole, another potent inhibitor, is predicted to increase the relative potency-adjusted unbound AUC of abemaciclib plus its active metabolites by 2.2-fold. In cancer patients, administration of a single 50 mg dose of abemaciclib (one-third the approved recommended dose of 150 mg) with clarithromycin 500 mg twice daily increased the relative potency-adjusted unbound AUC of abemaciclib plus its active metabolites by 2.5-fold relative to abemaciclib administered alone. The moderate CYP450 3A4 inhibitors, diltiazem and verapamil, are predicted to increase the relative potency-adjusted unbound AUC of abemaciclib plus its active metabolites by 2.4-fold and 1.6-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 abemaciclib may increase adverse effects such as nausea, vomiting, diarrhea, stomatitis, venous thromboembolism, hepatotoxicity, anemia, neutropenia, and thrombocytopenia.

Food has modest effects on the pharmacokinetics of abemaciclib. A high-fat, high-calorie meal (800 to 1000 calories; 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) administered to healthy subjects increased the Cmax and AUC of abemaciclib plus its active metabolites by 26% and 9%, respectively.

MANAGEMENT: Abemaciclib may be administered with or without food. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with abemaciclib.