Drug Interaction Report

MONITOR: Coadministration with pirtobrutinib may increase the plasma concentrations of drugs that are substrates of CYP450 2C8, 2C19, 3A4, P-glycoprotein (P-gp), and/or breast cancer resistance protein (BCRP). The peak plasma concentration (Cmax) and systemic exposure (AUC) of repaglinide, a CYP450 2C8 substrate, increased by 98% and 130%, respectively, and the Cmax and AUC of omeprazole, a CYP450 2C19 substrate, increased by 49% and 56%, respectively, when administered with pirtobrutinib. The Cmax and AUC of oral midazolam, a CYP450 3A4 substrate, increased by 58% and 70%, respectively, while exposure to IV midazolam was not significantly affected, when administered with pirtobrutinib. The Cmax and AUC of digoxin, a P-gp substrate, increased by 51% and 17%, respectively, when administered with a single pirtobrutinib dose (200 mg), and 55% and 35%, respectively, when administered with multiple pirtobrutinib doses (200 mg daily). The Cmax and AUC of rosuvastatin, a BCRP substrate, increased by 146% and 140%, respectively, when administered with pirtobrutinib. The risk of adverse reactions related to these substrates may be increased.

MANAGEMENT: Caution is advised if pirtobrutinib is used concomitantly with substrates of CYP450 2C8, 2C19, 3A4, P-gp, and/or BCRP, particularly sensitive substrates or those with a narrow therapeutic range. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration and for any dosage adjustments that 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.

GENERALLY AVOID: Acute ethanol ingestion may potentiate the CNS effects of many benzodiazepines. Tolerance may develop with chronic ethanol use. The mechanism may be decreased clearance of the benzodiazepines because of CYP450 hepatic enzyme inhibition. Also, it has been suggested that the cognitive deficits induced by benzodiazepines may be increased in patients who chronically consume large amounts of alcohol.

MANAGEMENT: Patients should be advised to avoid alcohol during benzodiazepine therapy.