Drug Interactions between amoxicillin / clarithromycin / omeprazole 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.

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.