Drug Interactions between acalabrutinib and lapatinib

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.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of lapatinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

ADJUST DOSING INTERVAL: Food can significantly increase the oral bioavailability of lapatinib. According to the manufacturer, lapatinib peak plasma concentration (Cmax) was approximately 2.5- and 3-fold higher and systemic exposure (AUC) 3- and 4-fold higher when administered with a low fat meal (5% fat; 500 calories) or with a high-fat meal (50% fat; 1000 calories), respectively, compared to fasting. Dividing the daily dose also resulted in an approximately 2-fold higher systemic exposure at steady state compared to the same total dose administered once daily.

MANAGEMENT: Patients treated with lapatinib should preferably avoid the consumption of grapefruit or grapefruit juice. The manufacturer recommends that lapatinib be administered at least one hour before or one hour after a meal. The lapatinib dose is administered once daily and should not be divided.