Drug Interaction Report

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of neratinib, which is primarily metabolized by the isoenzyme. According to the product labeling, when a single 240 mg oral dose of neratinib was administered with the potent CYP450 3A4 inducer rifampin in a study of 24 healthy volunteers, neratinib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 76% and 87%, respectively, compared to administration of neratinib alone. The AUC of two major active metabolites of neratinib were also reduced by 37% to 49% in the presence of rifampin. Simulations using physiologically-based pharmacokinetic (PBPK) models indicate that moderate CYP450 3A4 inducers may decrease the Cmax and AUC of neratinib by 12% and 32%, respectively.

MANAGEMENT: Given the potential for reduced efficacy of neratinib, concomitant use with potent or moderate inducers of CYP450 3A4 should generally be avoided. According to some authorities, if the CYP450 3A4 inducer cannot be avoided, the dose of neratinib should be increased to 320 mg once daily. The daily dose of neratinib should not exceed 320 mg. The previous dose of neratinib may be resumed following discontinuation of the CYP450 3A4 inducer.

GENERALLY AVOID: Grapefruit, grapefruit juice, grapefruit hybrids, pomelos, star-fruit, and Seville oranges may increase the plasma concentrations of neratinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in these fruits. Inhibition of hepatic CYP450 3A4 may also contribute. In a study consisting of 24 healthy subjects, neratinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 3.2- and 4.8-fold, respectively, when a single 240 mg oral dose of neratinib was administered with the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily for 5 days). Also, mean apparent oral clearance of neratinib decreased by approximately 75% and mean elimination half-life increased by 54%. The interaction has not been studied with these fruits. In general, for example, 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 neratinib may increase adverse effects such as diarrhea, nausea, vomiting, abdominal pain, stomatitis, anorexia, and hepatotoxicity.

Food with a high fat content enhances the oral bioavailability of neratinib. In healthy volunteers, administration of neratinib 240 mg with a high-fat meal (approximately 55% fat; 31% carbohydrate; 14% protein) increased neratinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.7- and 2.2-fold, respectively, compared to administration under fasting conditions. By contrast, a standard breakfast (approximately 50% carbohydrate; 35% fat; 15% protein) increased the Cmax and AUC of neratinib by 1.2- and 1.1-fold, respectively.

MANAGEMENT: The manufacturer recommends administering neratinib with food at approximately the same time every day. Patients should avoid consumption of grapefruit, grapefruit juice, grapefruit hybrids, pomelos, star-fruit, and Seville oranges during treatment with neratinib.