Drug Interactions between Jynarque and selpercatinib

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of selpercatinib. 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 a single dose of selpercatinib (160 mg) was coadministered with multiple doses of itraconazole (200 mg once daily), a potent CYP450 3A4 inhibitor, selpercatinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 30% and 133%, respectively. Based on pharmacokinetic modeling, administration of multiple doses of selpercatinib (160 mg twice daily) with multiple doses of the moderate CYP450 3A4 inhibitors diltiazem (60 mg three times daily), fluconazole (200 mg once daily), or verapamil (80 mg three times daily) is predicted to increase selpercatinib Cmax by 46% to 76% and AUC by 60% to 99%. 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 selpercatinib may increase the risk of serious adverse effects such as QT interval prolongation, liver transaminase and bilirubin elevations, hypertension, hemorrhage, edema, and hypersensitivity reactions (e.g., fever, rash, arthralgias/myalgias with concurrent decreased platelets or transaminitis).

MANAGEMENT: Until further information is available, it may be advisable for patients to limit or avoid consumption of grapefruit and grapefruit juice during treatment with selpercatinib.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of tolvaptan. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. According to the product labeling, administration of tolvaptan with grapefruit juice resulted in a 1.8-fold increase in tolvaptan systemic exposure. The clinical significance is unknown, although increased pharmacologic effects may be expected. Too rapid correction of hyponatremia increases the risk of osmotic demyelination syndrome, which is associated with dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, and death.

MANAGEMENT: Patients treated with tolvaptan should avoid consumption of grapefruits and grapefruit juice.