Drug Interaction Report

MONITOR: Coadministration of pirtobrutinib with antithrombotic agents may increase the risk of bleeding. According to the manufacturer, fatal hemorrhage occurred in 0.2% of patients treated with pirtobrutinib while Grade 3 or higher bleeding or any central nervous system bleeding occurred in 2.4% of patients treated with pirtobrutinib. Major hemorrhage occurred in 1.7% of patients taking pirtobrutinib without antithrombotic agents and 0.7% of patients taking pirtobrutinib with antithrombotic agents.

MANAGEMENT: Caution is advised if pirtobrutinib is used in patients taking antithrombotic agents. Consider the risks and benefits of antithrombotic agents when coadministered with pirtobrutinib and monitor patients for signs of bleeding. If bleeding occurs, dosage reduction or temporary or permanent discontinuation of pirtobrutinib may be required.

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.