Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 3A4 and/or P-glycoprotein (P-gp) may increase the plasma concentrations of apixaban, which is a substrate of both the isoenzyme and efflux transporter. When apixaban was coadministered with the moderate CYP450 3A4 and P-gp inhibitor diltiazem (360 mg once a day), mean apixaban peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.3- and 1.4-fold, respectively. Likewise, coadministration with the P-gp inhibitor naproxen (500 mg single dose) increased the mean apixaban Cmax and AUC by approximately 1.6- and 1.5-fold, respectively.

MANAGEMENT: No dosage adjustment for apixaban is required during concomitant therapy with lone inhibitors of CYP450 3A4 or P-gp, or moderate or weak dual inhibitors of both CYP450 3A4 and P-gp. However, caution may be advisable. Closer monitoring of the pharmacologic effects of apixaban may be appropriate whenever a CYP450 3A4 or P-gp inhibitor is added to or withdrawn from therapy. Patients should be routinely evaluated for signs and symptoms suggesting blood loss such as a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress (in pregnant women).

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.