Drug Interactions between amoxicillin / clarithromycin / omeprazole and neratinib

GENERALLY AVOID: Coadministration with potent or moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of neratinib, which is primarily metabolized by the isoenzyme. In a study with 24 healthy volunteers, administration of a single 240 mg oral dose of neratinib with the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily for 5 days) increased neratinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 3.2- and 4.8-fold, respectively, compared to administration of neratinib alone. Ketoconazole also reduced the mean apparent oral clearance of neratinib by 75% and increased its mean elimination half-life by approximately 6 hours. Simulations using physiologically-based pharmacokinetic (PBPK) models indicate that moderate CYP450 3A4 inhibitors may increase the Cmax and AUC of neratinib by 6% and 19%, respectively.

MANAGEMENT: Given the potential for increased risk of toxicity, concomitant use of neratinib with potent or moderate inhibitors of CYP450 3A4 should generally be avoided. According to some authorities, if the CYP450 3A4 inhibitor cannot be avoided, the dose of neratinib should be reduced to 40 mg once daily with a strong CYP450 3A4 inhibitor and 200 mg once daily with a moderate CYP450 3A4 inhibitor. The previous dose of neratinib may be resumed following discontinuation of a strong or moderate CYP450 3A4 inhibitor.

GENERALLY AVOID: Coadministration with proton pump inhibitors or H2-receptor antagonists may significantly decrease the oral bioavailability of neratinib. The solubility of neratinib is pH-dependent and increases as neratinib becomes protonated at acidic pH, thus an increase in pH may interfere with its absorption. According to the product labeling, neratinib is sparingly soluble at pH 1.2 (32.90 mg/mL) and insoluble at approximate pH 5.0 and above (0.08 mg/mL or less). When a single 240 mg dose of neratinib was administered to 15 healthy adult subjects on day 5 of treatment with lansoprazole 30 mg orally once daily for 7 days, mean neratinib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 71% and 65%, respectively, compared to neratinib administered alone. In addition, the Cmax and AUC of neratinib were reduced by 55% and 47%, respectively, when neratinib was administered 2 hours after a 300 mg dose of ranitidine.

MANAGEMENT: Concomitant use of neratinib with proton pump inhibitors and H2-receptor antagonists should generally be avoided. According to some authorities, if H2-receptor antagonist therapy is required, neratinib should be administered at least 2 hours before or 10 hours after the H2-receptor antagonist. In addition, short-acting antacids could be considered if acid-suppression therapy is required, with neratinib dosing separated by at least three hours after antacid administration. If coadministered with a gastric acid reducing agent, increasing the dose of neratinib is unlikely to compensate for the loss of bioavailability.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.