Drug Interaction Report

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.

ADJUST DOSING INTERVAL: Food significantly increases the oral bioavailability of pralsetinib. According to the product labeling, administration of pralsetinib (200 mg) with a high-fat meal (approximately 800 to 1000 calories; 50% to 60% from fat) increased mean pralsetinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 104% and 122%, respectively. The median time to maximum concentration (Tmax) was delayed from 4 hours to 8.5 hours, when compared to the fasted state.

GENERALLY AVOID: The juice of grapefruit and/or Seville oranges may increase the plasma concentrations of pralsetinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit and Seville oranges. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to pralsetinib may increase the risk 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: Pralsetinib should be administered on an empty stomach, with no food intake recommended for at least 2 hours before and at least 1 hour after taking the medication. Patients should avoid consumption of grapefruit, grapefruit juice, Seville oranges, or Seville orange juice during treatment with pralsetinib.

GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.

MANAGEMENT: The combination of ethanol and barbiturates should be avoided.