Drug Interactions between pemigatinib and Phyrago

GENERALLY AVOID: Grapefruit and grapefruit juice may significantly increase the plasma concentrations of dasatinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). 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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. Because dasatinib prolongs the QT interval, high plasma levels of dasatinib may increase the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

MANAGEMENT: Patients treated with dasatinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Some authorities recommend close monitoring for toxicity (e.g., myelosuppression, bleeding complications, fluid retention, bradycardia or other conduction disturbances) and a reduction of dasatinib dosage to a range of 20 to 40 mg daily should be considered if there are no alternatives and concomitant use with a potent CYP450 3A4 inhibitor is necessary.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of pemigatinib, which is primarily metabolized by CYP450 3A4 in vitro. 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 itraconazole, a potent CYP450 3A4 inhibitor, was administered following a single oral pemigatinib dose of 4.5 mg, pemigatinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 17% and 88%, respectively. Concomitant use of moderate CYP450 3A4 inhibitors is predicted to increase pemigatinib exposure by approximately 50% to 80%. 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 pemigatinib may increase the incidence and severity of serious adverse reactions such as hyperphosphatemia (which can cause precipitation of calcium-phosphate crystals over time that can lead to hypocalcemia, soft tissue mineralization such as cutaneous calcification and calcinosis, secondary hyperparathyroidism, anemia, muscle cramps, seizures, QT prolongation, and arrhythmias), serous retinal detachment (which may cause symptoms such as blurred vision, visual floaters, or photopsia), palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), arthralgia, stomatitis, diarrhea, nausea, vomiting, and constipation.

Pemigatinib pharmacokinetics were not significantly affected by coadministration of a high-fat, high-calorie meal (approximately 1000 calories; 500 to 600 calories from fat).

MANAGEMENT: Pemigatinib may be administered with or without food. Patients should avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit extract during treatment with pemigatinib.