Drug Interaction Report

MONITOR: Coadministration with inhibitors of the breast cancer resistance protein (BCRP) may increase the plasma concentrations and effects of seladelpar, which is a substrate of this efflux transporter. A clinical drug interaction study found that the systemic exposure (AUC) and maximum plasma concentration (Cmax) of a single dose of seladelpar (10 mg) increased by 2.1- and 2.9-fold, respectively, when administered with a single dose of the BCRP inhibitor cyclosporine (600 mg) in healthy subjects.

MANAGEMENT: Close monitoring for adverse reactions is advised if seladelpar is administered concurrently with a BCRP 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 this transporter even after the agent has been discontinued.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of pirtobrutinib, which is primarily metabolized by CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice but has been reported for other CYP450 3A4 inhibitors. When pirtobrutinib (200 mg single dose) was administered with itraconazole, a potent CYP450 3A4 inhibitor, pirtobrutinib systemic exposure (AUC) increased by 49%. Concomitant use of diltiazem or verapamil, moderate CYP450 3A4 inhibitors, is predicted to increase pirtobrutinib AUC by 20% and 30%, respectively. 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 pirtobrutinib may increase the risk of infection, bruising, bleeding, fatigue, musculoskeletal pain, diarrhea, edema, and dyspnea.

MANAGEMENT: It may be advisable for patients to avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with pirtobrutinib.