Drug Interaction Report

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.

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: Grapefruit and/or grapefruit juice may increase the systemic exposure to palbociclib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Increased exposure to palbociclib may increase the risk of adverse effects such as infections, neutropenia, leukopenia, anemia, thrombocytopenia, anorexia, nausea, vomiting, diarrhea, stomatitis, alopecia, asthenia, peripheral neuropathy, and epistaxis.

ADJUST DOSING INTERVAL: Food may enhance the oral bioavailability of palbociclib capsules and reduce the intersubject variability of palbociclib exposure. According to the product labeling, absorption and exposure of palbociclib from its oral capsule formulation were very low in approximately 13% of the population when taken in the fasted state. Food intake increased the palbociclib exposure in this small subset of the population but did not alter exposure in the rest of the population to a clinically relevant extent. Compared to palbociclib capsules given under overnight fasted conditions, the population average palbociclib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 38% and 21%, respectively, when given with high-fat, high-calorie food (approximately 800 to 1000 calories; 150, 250, and 500 to 600 calories from protein, carbohydrate and fat, respectively); by 27% and 12%, respectively, when given with low-fat, low-calorie food (approximately 400 to 500 calories; 120, 250, and 28 to 35 calories from protein, carbohydrate and fat, respectively); and by 24% and 13%, respectively, when given with moderate-fat, standard calorie food (approximately 500 to 700 calories; 75 to 105, 250 to 350 and 175 to 245 calories from protein, carbohydrate and fat, respectively) one hour before and two hours after palbociclib capsule dosing.

MANAGEMENT: Patients should avoid consumption of grapefruit or grapefruit juice while on treatment with palbociclib. To avoid variability in drug absorption between doses, palbociclib capsules should be taken with food. Palbociclib tablet formulations may be taken with or without food.