Drug Interactions between Digitek and mavorixafor

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.

Administration of digoxin with a high-fiber meal has been shown to decrease its bioavailability by almost 20%. Fiber can sequester up to 45% of the drug when given orally. Patients should be advised to maintain a regular diet without significant fluctuation in fiber intake while digoxin is being titrated.

Grapefruit juice may modestly increase the plasma concentrations of digoxin. The mechanism is increased absorption of digoxin due to mild inhibition of intestinal P-glycoprotein by certain compounds present in grapefruits. In 12 healthy volunteers, administration of grapefruit juice with and 30 minutes before, as well as 3.5, 7.5, and 11.5 hours after a single digoxin dose (0.5 mg) increased the mean area under the plasma concentration-time curve (AUC) of digoxin by just 9% compared to administration with water. Moreover, P-glycoprotein genetic polymorphism does not appear to influence the magnitude of the effects of grapefruit juice on digoxin. Thus, the interaction is unlikely to be of clinical significance.