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: Administration with grapefruit juice (compared to water or orange juice) has been shown to increase blood concentrations of cyclosporine with a relatively high degree of interpatient variability. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

GENERALLY AVOID: Administration with red wine or purple grape juice may decrease blood concentrations of cyclosporine. In 12 healthy volunteers, 12 ounces total of a merlot consumed 15 minutes prior to and during cyclosporine administration (single 8 mg/kg dose of Sandimmune) decreased cyclosporine peak blood concentration (Cmax) and systemic exposure (AUC) by 38% and 30%, respectively, compared to water. The time to reach peak concentration (Tmax) doubled, and oral clearance increased 50%. Similarly, one study were 12 healthy patients were administered purple grape juice and a single dose of cyclosporine showed a 30% and a 36% decrease in cyclosporine systemic exposure (AUC) and peak blood concentration (Cmax), respectively. The exact mechanism of interaction is unknown but may involve decreased cyclosporine absorption.

MONITOR: Food has been found to have variable effects on the absorption of cyclosporine. There have been reports of impaired, unchanged, and enhanced absorption during administration with meals relative to the fasting state. The mechanisms are unclear. Some investigators found an association with the fat content of food. In one study, increased fat intake resulted in significantly increased cyclosporine bioavailability and clearance. However, the AUC and pharmacodynamics of cyclosporine were not significantly affected, thus clinical relevance of these findings may be minimal.

MANAGEMENT: Patients receiving cyclosporine therapy should be advised to either refrain from or avoid fluctuations in the consumption of grapefruits and grapefruit juice. Until more data are available, the consumption of red wine or purple grape juice should preferably be avoided or limited. All oral formulations of cyclosporine should be administered on a consistent schedule with regard to time of day and relation to meals so as to avoid large fluctuations in plasma drug levels.