Drug Interactions between acalabrutinib and ibrutinib

GENERALLY AVOID: Coadministration with grapefruit, grapefruit juice, or Seville oranges may significantly increase the plasma concentrations of ibrutinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Pharmacokinetic modeling suggests that other moderate CYP450 3A4 inhibitors such as diltiazem and erythromycin may increase ibrutinib systemic exposure (AUC) by 6- to 9-fold under fasting condition. The safety and efficacy of these exposures are unknown. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 to 1400 mg) given for 28 days, which yielded single dose AUC values that were approximately 50% greater than steady-state exposures seen at the highest indicated dose of 560 mg.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of ibrutinib. The mechanism of interaction is unknown. According to the product labeling, administration with food increases ibrutinib exposure approximately 2-fold compared to administration after overnight fasting.

MANAGEMENT: Patients treated with ibrutinib should avoid consumption of Seville oranges, grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Ibrutinib should be taken once daily at approximately the same time each day.

GENERALLY AVOID: Consumption of grapefruit and/or grapefruit juice may increase the plasma concentrations of acalabrutinib. 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 specifically, but has been reported for other CYP450 3A4 inhibitors. When acalabrutinib was administered with the potent CYP450 3A4 inhibitor itraconazole (200 mg once daily for 5 days) in 17 healthy subjects, acalabrutinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 3.9- and 5.1-fold, respectively. Physiologically based pharmacokinetic (PBPK) simulations showed that moderate CYP450 3A4 inhibitors (erythromycin, fluconazole, diltiazem) increased acalabrutinib Cmax and AUC by 2- to nearly 3-fold. In healthy subjects, administration of acalabrutinib with the moderate CYP450 3A4 inhibitors fluconazole (400 mg as a single dose) or isavuconazole (200 mg as a repeated dose for 5 days) increased acalabrutinib Cmax and AUC by 1.4- to 2-fold, while the Cmax and AUC of the active metabolite, ACP-5862, was decreased by 0.65- to 0.88-fold. 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 acalabrutinib exposure may potentiate the risk of toxicities such as hemorrhage, infection, cytopenias, malignancies, and atrial fibrillation or flutter.

Food may delay the absorption of acalabrutinib, but does not appear to affect the overall extent of absorption. When a single 100 mg tablet or a 75 mg developmental formulation of acalabrutinib was administered with a high-fat, high-calorie meal (approximately 918 calories; 59 grams carbohydrate, 59 grams fat, 39 grams protein) in healthy study subjects, mean acalabrutinib Cmax was decreased by 54% and 73%, respectively, while time to reach Cmax was delayed by 1 to 2 hours compared to administration under fasted conditions. However, mean AUC was not affected.

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

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

• acalabrutinib
• ibrutinib

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.