Drug Interactions between ivacaftor / lumacaftor and pralsetinib

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.

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of pralsetinib, which is primarily metabolized by the isoenzyme. The peak plasma concentration (Cmax) and systemic exposure (AUC) of a single dose of pralsetinib (400 mg) decreased by 30% and 68%, respectively, when given concurrently with the potent CYP450 3A4 inducer rifampin (600 mg once daily). Reduced therapeutic efficacy may occur. 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 (e.g., apalutamide, encorafenib, enzalutamide, ivosidenib) or lead to elevations in liver transaminases (e.g., carbamazepine, fosphenytoin, mitotane, phenytoin, rifampin, rifapentine) may result in additive effects and an increased risk of serious side effects such as ventricular arrhythmias like torsade de pointes or hepatotoxicity.

MANAGEMENT: Concomitant use of pralsetinib with potent CYP450 3A4 inducers should generally be avoided. If coadministration is considered clinically necessary, the current dose of pralsetinib should be doubled starting on Day 7 of coadministration with the potent CYP450 3A4 inducer. If the CYP450 3A4 inducer also carries a risk of prolonging the QT interval, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval may be advisable. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate serious adverse effects including but not limited to hepatotoxicity and the occurrence of torsade de pointes. Once the potent CYP450 3A4 inducer has been discontinued for at least 14 days, the pralsetinib dose taken prior to initiating the potent CYP450 3A4 inducer may be resumed. Consult the product labeling for further guidance.