Drug Interactions between amoxicillin / clarithromycin / vonoprazan 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 inhibitors of CYP450 3A4 may increase the plasma concentrations of pralsetinib, which is primarily metabolized by the isoenzyme. A physiologically based pharmacokinetic (PBPK) model predicted pralsetinib's peak plasma concentration (Cmax) and systemic exposure (AUC) would increase by 1.2- and 2.2-fold, respectively, when coadministered with the potent CYP450 3A4 inhibitor voriconazole (400 mg twice daily on Day 1, followed by 200 mg twice daily). Similarly, another PBPK model predicted that concomitant use of the moderate CYP450 3A4 inhibitor fluconazole (400 mg daily) would increase the Cmax and AUC of pralsetinib by 1.2- and 1.7-fold, respectively. The extent to which other, less potent CYP450 3A4 inhibitors may interact with pralsetinib is unknown. Increased exposure to pralsetinib may increase the risk and/or frequency of 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: Caution is advised when pralsetinib is used with CYP450 3A4 inhibitors. Monitor closely for adverse effects whenever a CYP450 3A4 inhibitor is added to therapy. Alternative treatments may be required if an interaction is suspected.

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.