Drug Interactions between amoxicillin / clarithromycin / lansoprazole 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.

MONITOR: Coadministration with clarithromycin may increase the plasma concentrations of lansoprazole. The proposed mechanism is clarithromycin inhibition of intestinal (first-pass) and hepatic metabolism of lansoprazole via CYP450 3A4. Although lansoprazole is primarily metabolized by CYP450 2C19 in the liver, 3A4-mediated metabolism is the predominant pathway in individuals who are 2C19-deficient (approximately 3% to 5% of the Caucasian and 17% to 20% of the Asian population). Additionally, inhibition of P-glycoprotein intestinal efflux transporter by clarithromycin may also contribute to the interaction, resulting in increased bioavailability of lansoprazole. In 18 healthy volunteers--six each of homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs) of CYP450 2C19--clarithromycin (400 mg orally twice a day for 6 days) increased the peak plasma concentration (Cmax) of a single 60 mg oral dose of lansoprazole by 1.47, 1.71- and 1.52-fold, respectively, and area under the concentration-time curve (AUC) by 1.55-, 1.74- and 1.80-fold, respectively, in each of these groups compared to placebo. The AUC ratio of lansoprazole to lansoprazole sulphone, which is considered an index of CYP450 3A4 activity, was significantly increased by clarithromycin in all three groups. However, elimination half-life of lansoprazole was prolonged by 1.54-fold only in PMs. Mild diarrhea was reported in two subjects and mild abdominal disturbance in six subjects during clarithromycin coadministration. These side effects continued until day 6 and ameliorated the day after discontinuation of clarithromycin, whereas no adverse events were reported during placebo administration or after lansoprazole plus placebo. In another study, clarithromycin induced dose-dependent increases in the plasma concentration of lansoprazole in a group of 20 patients receiving treatment for H. pylori eradication. Mean 3-hour plasma lansoprazole concentration was 385 ng/mL for the control subjects who received lansoprazole 30 mg and amoxicillin 750 mg twice a day for 7 days; 696 ng/mL for patients coadministered clarithromycin 200 mg twice a day; and 947 ng/mL for patients coadministered clarithromycin 400 mg twice a day.

MANAGEMENT: Although lansoprazole is generally well tolerated, caution may be advised during coadministration with clarithromycin, particularly if higher dosages of one or both drugs are used. Dosage adjustment may be necessary in patients who experience excessive adverse effects of lansoprazole.

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.