Drug Interaction Report

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of pirtobrutinib, which is primarily metabolized by the isoenzyme. When pirtobrutinib (200 mg single dose) was administered with rifampin, a potent CYP450 3A4 inducer, pirtobrutinib systemic exposure (AUC) decreased by 71%. Concomitant use of bosentan or efavirenz, moderate CYP450 3A4 inducers, is predicted to decrease pirtobrutinib AUC by 27% and 49%, respectively. Reduced effectiveness of pirtobrutinib may result.

MANAGEMENT: Coadministration of pirtobrutinib and potent or moderate CYP450 3A4 inducers should be avoided. If concomitant use of a moderate CYP450 3A4 inducer is unavoidable and the current dosage of pirtobrutinib is 200 mg once daily, increase the dose to 300 mg. If the current dosage of pirtobrutinib is 50 mg or 100 mg once daily, increase the dose by 50 mg.

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.