Drug Interaction Report

MONITOR: Concomitant use with a moderate to potent CYP450 3A4 inhibitor may significantly increase seladelpar's exposure in patients who are CYP450 2C9 poor metabolizers. The proposed mechanism is reduced clearance of seladelpar, which is primarily metabolized via CYP450 2C9 and to a lesser extent via CYP450 3A4 and 2C8. The activity of CYP450 2C9 is decreased in individuals with genetic variants of the isoenzyme. After a single dose of seladelpar (1 mg to 15 mg), dose-normalized systemic exposure (AUC) was 48% higher in CYP450 2C9 poor metabolizers (n=2) and 24% higher in CYP450 2C9 intermediate metabolizers (n=28) compared to normal metabolizers (n=84). However, the maximum plasma concentration (Cmax) was similar regardless of metabolizer status. These increases in AUC are not considered clinically relevant alone. Similarly, physiologically based pharmacokinetic model simulations predicted that coadministration with the potent CYP450 3A4 inhibitor itraconazole (300 mg daily) and the moderate CYP450 3A4 inhibitor erythromycin (500 mg 4 times daily) increased seladelpar's AUC by 34% and 24% and its Cmax by 18% and 14%, respectively. These changes were also not considered clinically relevant alone. However, use of a concomitant moderate to potent CYP450 3A4 inhibitor in a patient classified as a CYP450 2C9 poor metabolizer may result in clinically significant changes. While in vivo data specific to this scenario are lacking, coadministration with the moderate CYP450 2C9 and 3A4 inhibitor fluconazole (400 mg) increased the AUC of seladelpar (10 mg) by 2.4-fold, which was considered clinically significant.

MANAGEMENT: If concomitant use of a moderate to potent CYP450 3A4 inhibitor is clinically necessary during treatment with seladelpar, caution and determining the patient's CYP450 2C9 genotype may be advisable. Patients who are classified as poor CYP450 2C9 metabolizers should be monitored more closely for adverse reactions (e.g., abnormal liver function tests) during coadministration. Should adverse reactions occur, treatment with seladelpar may need to be held or permanently discontinued as indicated by the manufacturer. The labeling of the inhibitor should also be consulted as some inhibitors may continue to have effects on CYP450 3A4 even after the agent has been discontinued.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ceritinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because ceritinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death. Other, more common side effects such as diarrhea, nausea, vomiting, abdominal pain, hyperglycemia, and bradycardia may also increase.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of ceritinib. The mechanism of interaction is unknown. Compared to the fast state, administration of a single 500 mg dose of ceritinib with a high-fat meal (approximately 1000 calories; 58 grams of fat) increased ceritinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 41% and 73%, respectively, and administration with a low-fat meal (approximately 330 calories; 9 grams of fat) increased ceritinib Cmax and AUC by 43% and 58%, respectively. A dose of 600 mg or higher taken with a meal is expected to produce systemic exposure exceeding that from a 750 mg dose taken in the fasted state, which may lead to increased adverse effects.

MANAGEMENT: Patients treated with ceritinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Ceritinib should be administered on an empty stomach (i.e., avoid administration within 2 hours of a meal).