Drug Interactions between nirmatrelvir / ritonavir 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.

GENERALLY AVOID: Coadministration with P-glycoprotein (P-gp) inhibitors and/or moderate CYP450 3A4 inhibitors may significantly increase the plasma concentrations of pralsetinib, which is both a substrate of the P-gp efflux transporter and primarily metabolized by CYP450 3A4. Physiologically based pharmacokinetic (PBPK) modeling was used to evaluate these potential interactions. Coadministration of a single dose of the P-gp inhibitor cyclosporine (600 mg) is predicted to increase the peak plasma concentration (Cmax) and systemic exposure (AUC) of pralsetinib (200 mg) by 1.5- and 1.8-fold, respectively. Likewise, concomitant use of the moderate CYP450 3A4 inhibitor fluconazole (400 mg once daily) is predicted to increase the Cmax and AUC of pralsetinib by 1.2- and 1.7-fold, respectively. Similarly, coadministration with the combined P-gp and moderate CYP450 3A4 inhibitor verapamil (80 mg three times daily) is predicted to increase the Cmax and AUC of pralsetinib by 1.6- and 2.1-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 P-gp inhibitors, moderate CYP450 3A4 inhibitors, or combined P-gp and moderate CYP450 3A4 inhibitors should be avoided when possible. If coadministration is necessary, the manufacturer recommends reducing the dose of pralsetinib as follows: 300 mg once daily for patients receiving 400 mg once daily, 200 mg once daily for patients receiving 300 mg once daily, and 100 mg once daily for patients receiving 200 mg once daily. Additional dose adjustments may be required depending on the ability of the patient to tolerate the combination. Following discontinuation of the P-gp inhibitor, moderate CYP450 3A4 inhibitor, or combined P-gp and moderate CYP450 3A4 inhibitor, and after an appropriate washout period (3 to 5 elimination half-lives), the pralsetinib dose taken prior to initiating the inhibitor may be resumed. The product labeling of the co-administered drug should also be consulted for further guidance; for example, in instances when its inhibitory profile may be affected by dose or dosage form.