Drug Interactions between abrocitinib and pacritinib

GENERALLY AVOID: Theoretically, coadministration with grapefruit juice may increase the plasma concentrations of pacritinib, 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 the potent CYP450 3A4 inhibitor, clarithromycin. In a clinical drug interaction study, a single dose of pacritinib (400 mg) was administered following treatment with clarithromycin (500 mg twice daily for 5 days). The peak plasma concentration (Cmax) and systemic exposure (AUC) of pacritinib increased by 30% and 80%, respectively, compared to pacritinib administered alone. Longer treatment with clarithromycin that results in maximal CYP450 3A4 inhibition may increase pacritinib exposure even higher. 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 pacritinib may increase the risk of adverse effects such as diarrhea, thrombocytopenia, infection, and QT prolongation.

Pacritinib pharmacokinetics were not significantly affected when administered with a high-fat meal.

MANAGEMENT: Although clinical data are lacking, it may be advisable to avoid consumption of grapefruit or grapefruit juice during treatment with pacritinib. Pacritinib may be administered with or without food.

MONITOR: Smoking during treatment with abrocitinib may increase the risk of major adverse cardiovascular events (MACE) and the risk of developing malignancies. During abrocitinib clinical studies, current or past smokers had an additional increased risk of overall malignancies. Also, abrocitinib may increase patients' risk of MACE, including myocardial infarction, stroke, and cardiovascular death.

Administration of abrocitinib with high-fat, high-calorie food increased abrocitinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 29% and 26%, respectively, and prolonged the time to reach Cmax by 2 hours. These changes are not considered clinically relevant.

MANAGEMENT: Caution is advised if abrocitinib is prescribed to current or past smokers. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. The manufacturer recommends discontinuing abrocitinib in patients that have experienced a myocardial infarction or stroke. Abrocitinib may be taken with or without food.