Drug Interactions between Jaypirca and trabectedin

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: Coadministration with grapefruit juice may increase the plasma concentrations of trabectedin. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

GENERALLY AVOID: Coadministration of trabectedin with other agents known to induce hepatotoxicity such as alcohol may potentiate the risk of liver injury. Reversible, acute increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have occurred frequently in patients treated with trabectedin alone or with pegylated liposomal doxorubicin in clinical trials. In one U.S. trial with 378 patients, grade 3 or 4 elevated liver function tests (defined as elevations in ALT, AST, total bilirubin, or alkaline phosphatase) were reported in 35% of patients receiving trabectedin. ALT or AST elevations greater than eight times the upper limit of normal (ULN) occurred in 18% of patients, and drug-induced liver injury (defined as concurrent elevations in ALT or AST more than three times ULN, alkaline phosphatase less than two times ULN, and total bilirubin at least two times ULN) occurred in 1.3% of patients.

MANAGEMENT: Consumption of grapefruit or grapefruit juice during treatment with trabectedin should be avoided. Excessive use of alcohol is also not recommended. Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. Monitoring of alkaline phosphatase, bilirubin, AST, and ALT should occur regularly during trabectedin treatment in accordance with the product labeling, or as often as necessary when clinical symptoms develop. Trabectedin must not be used in patients with elevated bilirubin at the time of initiation of cycle. Elevated liver function tests should be managed with treatment interruption, dosage reduction, or permanent discontinuation depending on the severity and duration of abnormality.