Drug Interactions between imatinib 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.

GENERALLY AVOID: Coadministration of imatinib with strong CYP450 3A4 inhibitors such as grapefruit juice, may significantly increase the plasma concentrations of imatinib, a known substrate of CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of imatinib by certain compounds present in grapefruits. 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. In a single-dose study, coadministration of imatinib with ketoconazole (a strong CYP450 3A4 inhibitor) increased imatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 26% and 40%, respectively.

MANAGEMENT: Patients treated with imatinib should preferably avoid the consumption of grapefruit or grapefruit juice. If coadministration is unavoidable, monitor for prolonged and/or increased pharmacologic effects of imatinib, including edema, hematologic toxicity and immunosuppression.