Drug Interactions between mavorixafor and ubrogepant

GENERALLY AVOID: Grapefruit products may significantly increase the plasma concentrations and effects of mavorixafor, which is primarily metabolized by the isoenzyme CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. A study examining mavorixafor in combination with the strong CYP450 3A4 and P-glycoprotein inhibitor, itraconazole, suggests an increase in mavorixafor's systemic exposure (AUC) of approximately 2-fold. Clinical data with grapefruit products are not available. Pharmacokinetic interactions involving grapefruit are subject to a high degree of interpatient variability and can also be affected by the product and amount consumed; therefore, the extent to which a given patient may be affected is difficult to predict. Additionally, since mavorixafor is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

ADJUST DOSING INTERVAL: Food may significantly reduce the peak plasma concentration (Cmax) and systemic exposure (AUC) of mavorixafor. When a single-dose of mavorixafor (400 mg) was administered with a high-fat meal (1000 calories, 50% fat) to healthy subjects, the Cmax and AUC decreased by 66% and 55%, respectively. Similarly, when the same dose was given with a low-fat meal (500 calories, 25% fat) to healthy subjects, mavorixafor's Cmax and AUC decreased by 55% and 51%, respectively. Additionally, a single dose of mavorixafor (400 mg) administered with a low-fat meal to healthy subjects following an overnight fast resulted in a 14% higher Cmax and an 18% lower AUC than those obtained from subjects who fasted for an additional 4 hours after the dose.

MANAGEMENT: Mavorixafor should be taken on an empty stomach after an overnight fast, 30 minutes before food. Patients should be advised to avoid eating or drinking products containing grapefruit, as this could increase the risk of experiencing adverse effects from mavorixafor such as QT prolongation.

ADJUST DOSE: Grapefruit and grapefruit juice may increase the plasma concentrations of ubrogepant. 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 but has been reported for other CYP450 3A4 inhibitors. When ubrogepant was administered with the potent CYP450 3A4 inhibitor ketoconazole during in vivo studies, ubrogepant peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 5.3- and 9.7-fold, respectively. When administered with the moderate CYP450 3A4 inhibitor verapamil, ubrogepant Cmax and AUC increased by 2.8- and 3.5-fold, respectively. 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.

When administered with a high-fat meal, ubrogepant time to maximum plasma concentration (Tmax) was delayed by 2 hours, which resulted in a 22% decrease in Cmax and no change in AUC. Ubrogepant was administered without regard to food in clinical efficacy studies.

MANAGEMENT: Ubrogepant may be administered with or without food. When coadministered with grapefruit or grapefruit juice, the manufacturer recommends an initial ubrogepant dose of 50 mg. A second dose, if needed, should not be administered within 24 hours of the initial dose.