Drug Interactions between amoxicillin / clarithromycin / omeprazole and pralsetinib

GENERALLY AVOID: Coadministration with a combined P-glycoprotein (P-gp) and potent CYP450 3A4 inhibitor may significantly increase the plasma concentrations of pralsetinib, which, based on in vitro data, is both a substrate of the P-gp efflux transporter and primarily metabolized by CYP450 3A4. In a clinical drug interaction study in healthy participants, coadministration of a single dose of pralsetinib (200 mg on Day 4) with the combined P-gp and potent CYP450 3A4 inhibitor itraconazole (200 mg twice daily on Day 1, then 200 mg daily for 13 days) increased the peak plasma concentration (Cmax) and systemic exposure (AUC ) of pralsetinib by 1.8- and 3.5-fold, respectively. Increased exposure to pralsetinib may increase the risk of serious adverse effects such as interstitial lung disease/pneumonitis, liver transaminase elevations, hypertension, and hemorrhage. Some clinical trials have also observed prolongation of the QT interval in patients on pralsetinib, though this was not observed in a study of 34 patients with rearranged during transfection (RET)-altered solid tumors on pralsetinib at the recommended dosage.

MANAGEMENT: Concomitant use of pralsetinib with a combined P-gp and potent CYP450 3A4 inhibitor should be avoided when possible. If coadministration is clinically necessary, the manufacturer recommends reducing the dose of pralsetinib to 200 mg once daily for patients receiving 300 mg or 400 mg once daily and reducing the pralsetinib dose to 100 mg once daily for patients receiving 200 mg once daily. Additional monitoring for adverse effects may also be advisable. Following discontinuation of the combined P-gp and potent CYP450 3A4 inhibitor, and after an appropriate washout period (3 to 5 elimination half-lives), the pralsetinib dose taken prior to initiating the combined P-gp and potent CYP450 3A4 inhibitor may be resumed.

MONITOR: Coadministration with pralsetinib may alter the plasma concentrations of drugs that are substrates of CYP450 2C8, 2C9, 3A4, and/or 3A5. In vitro studies indicate that pralsetinib is both an inhibitor as well as an inducer of CYP450 2C8, 2C9, 3A4, and 3A5. Therefore, pralsetinib may decrease clearance via inhibition or increase clearance via induction of these isoenzymes, resulting in increased or decreased plasma concentrations of agents that are metabolized by one or more of these isoenzymes. Clinical and pharmacokinetic data are currently lacking.

MANAGEMENT: Caution is advised if pralsetinib is used concomitantly with drugs that are substrates of CYP450 2C8, 2C9, 3A4, and/or 3A5, particularly sensitive substrates or those with a narrow therapeutic range. Some authorities recommend avoiding coadministration of pralsetinib with CYP450 2C8, 2C9, 3A4, and/or 3A5 substrates for which minimal concentration changes may lead to therapeutic failure or serious toxicities. If coadministration is required, dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever pralsetinib is added to or withdrawn from therapy. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration and for any dosage adjustments that may be required.

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.