Drug Interactions between amoxicillin / clarithromycin / lansoprazole and pexidartinib

GENERALLY AVOID: Coadministration of pexidartinib with strong CYP450 3A4 inhibitors and/or uridine diphosphate glucuronosyltransferase (UGT) inhibitors may significantly increase the plasma concentrations and the incidence and severity of adverse effects of pexidartinib, including potentially fatal hepatotoxicity. The proposed mechanism is inhibition of CYP450 3A4 and/or UGT, the primary isoenzymes responsible for the metabolic clearance of pexidartinib. Concomitant administration of itraconazole, a strong CYP450 3A4 inhibitor, increased pexidartinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 48% and 70%, respectively. Coadministration with probenecid, a UGT inhibitor, increased pexidartinib Cmax and AUC by 5% and 60%, respectively.

MANAGEMENT: The use of pexidartinib with strong CYP450 3A4 inhibitors and/or UGT inhibitors should generally be avoided. If concomitant use is required, the dose of pexidartinib should be reduced according to the manufacturer's recommendations. If concomitant use of a strong CYP450 3A4 inhibitor or UGT inhibitor is discontinued, the dose of pexidartinib may be increased, after 3 plasma half-lives of the strong CYP450 3A4 inhibitor or UGT inhibitor, to the dose that was used prior to starting the strong CYP450 3A4 inhibitor or UGT inhibitor.

GENERALLY AVOID: Coadministration with proton pump inhibitors (PPIs) may significantly decrease the bioavailability and therapeutic effects of pexidartinib. The proposed mechanism is a pH-dependent reduction in drug dissolution and/or absorption. Concomitant administration of esomeprazole, a proton pump inhibitor, decreased pexidartinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 55% and 50%, respectively. The effect of coadministration with an H2-receptor antagonist or locally-acting antacids on pexidartinib pharmacokinetics is unknown.

MANAGEMENT: Concomitant use of pexidartinib with proton pump inhibitors should be avoided. If acid-suppression therapy is required, pexidartinib may be administered 2 hours before or 2 hours after taking a locally-acting antacid, or if using an H2-receptor antagonist, administer pexidartinib at least 2 hours before or 10 hours after taking the H2-receptor antagonist.

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.