Drug Interactions between aliskiren and fedratinib

GENERALLY AVOID: Coadministration with orange, apple, or grapefruit juice may significantly decrease the oral bioavailability and renin-inhibiting effect of aliskiren. The exact mechanism of interaction is unknown, but may include inhibition of OATP2B1-mediated influx of aliskiren in the small intestine, formation of insoluble complexes between fruit juice constituents and aliskiren, and/or increased ionization of aliskiren due to reduced intestinal pH. In 12 healthy volunteers, 200 mL of either orange juice or apple juice administered three times daily for 5 days in combination with a single 150 mg oral dose of aliskiren on day 3 reduced the mean aliskiren peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 80% and 60%, respectively, compared to water. Plasma renin activity was 87% and 67% higher at 24 hours postdose when aliskiren was administered with orange juice and apple juice, respectively, compared to water. No significant differences were observed in the blood pressure or heart rate between treatments. However, this may be due to the delayed onset of aliskiren's blood pressure-lowering effect, which would not be apparent following a single dose. A similar pharmacokinetic interaction has been reported with grapefruit juice. In 11 healthy volunteers, 200 mL of normal strength grapefruit juice administered three times daily for 5 days in combination with a single 150 mg oral dose of aliskiren on day 3 reduced the mean aliskiren Cmax and AUC by 81% and 61%, respectively, but there was no change in plasma renin activity compared to water. A high degree of interpatient variability was observed with all three interactions.

MONITOR: High-fat meals can substantially reduce the gastrointestinal absorption of aliskiren. According to the product labeling, administration of aliskiren with a high-fat meal decreased the mean peak plasma concentration (Cmax) and systemic exposure (AUC) by 85% and 71%, respectively. In clinical trials, however, aliskiren was administered without a fixed requirement in relation to meals.

MANAGEMENT: To ensure steady systemic drug levels and therapeutic effects, patients should establish a routine pattern for administration of aliskiren with regard to meals. Coadministration with orange, apple, or grapefruit juice should be avoided, especially if these juices are to be consumed on a regular basis or shortly before or after aliskiren dosing.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of fedratinib. 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 a single 300 mg oral dose of fedratinib (0.75 times the recommended dose) was coadministered with 200 mg twice daily ketoconazole, a potent CYP450 3A4 inhibitor, fedratinib total systemic exposure (AUC(inf)) increased by approximately 3-fold. Using physiologically based pharmacokinetic (PBPK) simulations, coadministration of fedratinib 400 mg once daily and ketoconazole 400 mg once daily is predicted to increase fedratinib AUC at steady state by 2-fold. Coadministration with the moderate CYP450 3A4 inhibitors, erythromycin (500 mg three times daily) or diltiazem (120 mg twice daily), is predicted to increase fedratinib AUC by approximately 1.5- to 2-fold following single-dose administration and by approximately 1.2-fold at steady state. 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 fedratinib exposure may potentiate the risk of adverse reactions such as nausea, vomiting, diarrhea, anemia, thrombocytopenia, neutropenia, encephalopathy (including Wernicke's), liver (ALT, AST) and pancreatic (amylase, lipase) enzyme elevations, increased blood creatinine, and secondary malignancies.

Food does not affect the oral bioavailability of fedratinib to a clinically significant extent. Administration of a single 500 mg dose (1.25 times the recommended dose) with a low-fat, low-calorie meal (162 calories; 6% from fat, 78% from carbohydrate, 16% from protein) or a high-fat, high-calorie meal (815 calories; 52% from fat, 33% from carbohydrate, 15% from protein) increased fedratinib peak plasma concentration (Cmax) and systemic exposure (AUC) by up to 14% and 24%, respectively.

MANAGEMENT: Fedratinib may be taken with or without food. However, administration with a high-fat meal may help reduce the incidence of nausea and vomiting. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with fedratinib.