Drug Interaction Report

MONITOR: Coadministration with a CYP450 3A4 inhibitor may increase the systemic exposure (AUC) of lurbinectedin, which is metabolized by the isoenzyme in vitro. In a Phase 1 study, coadministration of aprepitant, a moderate CYP450 3A4 inhibitor, decreased lurbinectedin plasma clearance by 33% compared to lurbinectedin alone. Increased exposure may increase the incidence and severity of adverse reactions of lurbinectedin, such as myelosuppression and hepatotoxicity. Data are not available for other, less potent inhibitors.

MANAGEMENT: Clinical and laboratory monitoring is advised whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy with lurbinectedin. Patients should be advised to contact their physician if they experience symptoms suggestive of myelosuppression or hepatotoxicity, such as fever or any other signs of infection, unusual bruising or bleeding; or nausea or vomiting, or pain on the right side of the abdomen.

GENERALLY AVOID: Grapefruit and Seville oranges may increase the plasma concentrations of lurbinectedin. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit and Seville oranges. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit or Seville oranges, but pharmacokinetic data are available for potent and moderate CYP450 3A4 inhibitors. In a clinical drug interaction study, coadministration of itraconazole, a potent CYP450 3A4 inhibitor, increased the systemic exposure (AUC) of total lurbinectedin by 2.7-fold and unbound lurbinectedin by 2.4-fold. In a Phase 1 study, coadministration of aprepitant, a moderate CYP450 3A4 inhibitor, decreased lurbinectedin plasma clearance by 33% compared to lurbinectedin alone. In general, the effect of grapefruit and Seville oranges is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice and Seville oranges (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 may increase the incidence and severity of adverse reactions of lurbinectedin, such as myelosuppression and hepatotoxicity.

MANAGEMENT: Patients should avoid consumption of grapefruit, grapefruit juice, and Seville oranges during treatment with lurbinectedin.