Drug Interaction Report

MONITOR: Concomitant administration with a dual moderate CYP450 2C9 and moderate to potent CYP450 3A4 inhibitor may significantly increase the plasma concentrations and effects of seladelpar, which is primarily metabolized via CYP450 2C9 and to a lesser extent via CYP450 3A4 and 2C8. When administered with the moderate CYP450 2C9 and 3A4 inhibitor fluconazole (400 mg) in healthy subjects, the systemic exposure (AUC) and maximum plasma concentration (Cmax) of a single dose of seladelpar (10 mg) increased by 2.4- and 1.4-fold, respectively. Clinical data with agents capable of moderate CYP450 2C9 and potent CYP450 3A4 inhibition are not available.

MANAGEMENT: Caution and close monitoring are advised if seladelpar is administered concurrently with a dual moderate CYP450 2C9 and moderate to potent CYP450 3A4 inhibitor. Liver tests should be monitored as clinically indicated and treatment with seladelpar may need to be held or permanently discontinued if liver tests worsen and/or clinical hepatitis develops. The labeling of the inhibitor should also be consulted as some inhibitors may continue to have effects on these isoenzymes even after the agent has been discontinued.

ADJUST DOSING INTERVAL: Food may significantly increase the plasma concentrations of mifepristone.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of mifepristone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: When mifepristone is used daily to control hyperglycemia secondary to hypercortisolism in patients with endogenous Cushing's syndrome, it should be taken with food to achieve consistent plasma drug levels. Patients should be advised to avoid consuming grapefruit or grapefruit juice during treatment with mifepristone, as it may cause increased adverse effects such as headache, dizziness, fatigue, nausea, vomiting, cramping, diarrhea, hypokalemia, adrenal insufficiency, vaginal bleeding, arthralgia, peripheral edema, and hypertension. Because mifepristone is eliminated slowly from the body, the interaction with grapefruit juice may be observed for a prolonged period.