Drug Interactions between clomipramine 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: Limited data suggest that the administration of clomipramine with grapefruit juice or cranberry juice may significantly increase plasma drug concentrations of clomipramine. Clomipramine is initially demethylated by CYP450 1A2, 3A3 and 3A4 before undergoing further metabolism to 8-hydroxyclomipramine. The increase in clomipramine bioavailability may stem from inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The precise mechanism by which cranberry juice exerts its effects is unknown, but may involve inhibition of CYP450 isoenzymes. This interaction has occasionally been exploited in attempts to improve symptomatic control of obsessive compulsive disorder.

MANAGEMENT: Patients receiving clomipramine therapy who ingest cranberry juice, grapefruits, or grapefruit juice should be monitored for adverse effects and undue fluctuations in plasma drug levels.

GENERALLY AVOID: The combination of ethanol and a tricyclic antidepressant may result in additive impairment of motor skills, especially driving skills. Also, one study has suggested that clomipramine metabolism is significantly impaired for several weeks or more following discontinuation of chronic alcohol consumption.

MANAGEMENT: Patients should be warned of this interaction and advised to limit their ethanol intake while taking tricyclic antidepressants. Monitoring for TCA toxicity (CNS depression, excessive anticholinergic effects, hypotension, arrhythmias) is recommended during alcohol withdrawal.