Drug Interactions between amoxicillin / clarithromycin / lansoprazole and selpercatinib

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of selpercatinib, which is primarily metabolized by the isoenzyme. When a single dose of selpercatinib (160 mg) was coadministered with multiple doses of itraconazole (200 mg once daily), a potent CYP450 3A4 inhibitor, selpercatinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 30% and 133%, respectively. Increased exposure to selpercatinib may increase the risk of serious adverse effects such as QT interval prolongation, liver transaminase and bilirubin elevations, hypertension, hemorrhage, edema, and hypersensitivity reactions (e.g., fever, rash, arthralgias/myalgias with concurrent decreased platelets or transaminitis). In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, coadministration with other agents that can prolong the QT interval may result in additive effects and an increased risk of ventricular arrhythmias like torsade de pointes.

MANAGEMENT: Concomitant use of selpercatinib with potent CYP450 3A4 inhibitors should be avoided when possible. However, if coadministration is required, a dosage reduction of selpercatinib is advised. The manufacturer's product labeling should be consulted for specific dosage modification recommendations for concomitant use of selpercatinib with potent CYP450 3A4 inhibitors. Close monitoring for adverse effects is advisable, including more frequent ECGs and laboratory monitoring of liver enzymes, bilirubin, electrolytes, glucose, and blood counts. Selpercatinib treatment should be discontinued, interrupted, or dosage reduced in patients with serious or life-threatening toxicities in accordance with the product labeling. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, the selpercatinib dosage that was taken prior to initiating the inhibitor may be resumed.

GENERALLY AVOID: Coadministration with drugs that increase gastric pH may significantly decrease the oral bioavailability of selpercatinib and reduce its concentrations in plasma. According to the product labeling, the aqueous solubility of selpercatinib is pH-dependent, from freely soluble at low pH to slightly soluble at neutral pH. When a single dose of selpercatinib (160 mg) was administered under fasted conditions with multiple daily doses of omeprazole (40 mg once daily), selpercatinib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 88% and 69%, respectively, compared to selpercatinib administered alone while fasting. These changes may result in diminished anti-tumor activity of selpercatinib. By contrast, when selpercatinib was administered with a high-fat meal (approximately 800 to 1000 calories;150 calories from protein, 250 calories from carbohydrate, 500 to 600 calories from fat) or a low-fat meal (approximately 390 calories; 10 g fat) in combination with multiple daily doses of omeprazole, selpercatinib Cmax was reduced by 49% and 22%, respectively, but AUC was not significantly altered.

MANAGEMENT: Concomitant use of selpercatinib with proton pump inhibitors should generally be avoided. If coadministration is required, the manufacturer recommends taking selpercatinib with food or a meal to minimize the clinical impact of the interaction.

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.