Drug Interaction Report

CONTRAINDICATED: Coadministration with inhibitors of CYP450 2D6 may significantly increase the plasma concentrations of eliglustat, which is primarily metabolized by CYP450 2D6 and, to a lesser extent, CYP450 3A4. Eliglustat at substantially elevated plasma concentrations is predicted to cause prolongation of the PR, QTc and QRS cardiac intervals, which may increase the risk of bradycardia, atrioventricular block, cardiac arrest, and serious ventricular arrhythmias such as torsade de pointes. In 30 subjects who were CYP450 2D6 extensive metabolizers (EMs), eliglustat peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 7.0- and 8.0-fold, respectively, following coadministration of eliglustat (84 mg twice daily) with the potent CYP450 2D6 inhibitor paroxetine (30 mg once daily). Simulations using physiologically-based pharmacokinetic (PBPK) models suggest that paroxetine may increase eliglustat Cmax by 2.1-fold and AUC by 2.3-fold in CYP450 2D6 intermediate metabolizers (IMs). When the moderate CYP450 2D6 inhibitor terbinafine was used, PBPK modeling predicted a 3.8-fold increase in eliglustat Cmax and 4.5-fold increase in AUC for EMs, and a 1.6-fold increase each in Cmax and AUC for IMs. The magnitude of interaction is expected to increase further with the addition of a CYP450 3A4 inhibitor like ketoconazole. Simulations using PBPK models suggest that the combination of paroxetine (30 mg once daily) and ketoconazole (400 mg once daily) may increase eliglustat Cmax by 16.7-fold and AUC by 24.2-fold in EMs given eliglustat 84 mg twice daily. For IMs, the estimated increases in eliglustat Cmax and AUC are 7.5- and 9.8-fold, respectively. When a less potent combination of CYP450 2D6 (terbinafine) and 3A4 (fluconazole) inhibitors were used, PK modeling predicted a 10.2-fold increase in eliglustat Cmax and 13.6-fold increase in AUC for EMs given eliglustat 84 mg twice daily, and a 4.2-fold increase in eliglustat Cmax and 5.0-fold increase in AUC for IMs.

MANAGEMENT: The use of eliglustat in combination with one or more drugs that may result in moderate or potent inhibition of both CYP450 2D6 and 3A4 is considered contraindicated in CYP450 2D6 intermediate metabolizers (IMs) and extensive metabolizers (EMs). In the absence of a concomitant CYP450 3A4 inhibitor, eliglustat may be prescribed at a reduced dosage of 84 mg once daily to IMs and EMs treated with a potent or moderate CYP450 2D6 inhibitor. Poor metabolizers are not affected by CYP450 2D6 inhibition (since they already have minimal functional levels of the isoenzyme) and may also receive the reduced dosage of eliglustat, so long as they are not treated with a CYP450 3A4 inhibitor. Potent and moderate CYP450 3A4 inhibitors include azole antifungal agents, protease inhibitors, aprepitant, ciprofloxacin, clarithromycin, cobicistat, conivaptan, crizotinib, delavirdine, diltiazem, dronedarone, erythromycin, fusidic acid, idelalisib, imatinib, lomitapide, mibefradil, mifepristone, nefazodone, ranolazine, telithromycin, and verapamil. Potent and moderate CYP450 2D6 inhibitors include abiraterone, bupropion, celecoxib, cimetidine, cinacalcet, clobazam, darifenacin, diphenhydramine, duloxetine, fluoxetine, givosiran, mavorixafor, methotrimeprazine, mirabegron, panobinostat, paroxetine, propoxyphene, quinidine, ranolazine, rolapitant, sertraline, stiripentol, and terbinafine. Some drugs such as abiraterone, cimetidine, mavorixafor, ranolazine, and stiripentol are dual CYP450 2D6 and 3A4 inhibitors, and they should probably not be used with eliglustat in any patient regardless of their CYP450 2D6 metabolizer status. In addition, antiarrhythmics such as amiodarone, dronedarone, flecainide, propafenone, and quinidine can inhibit CYP450 2D6 and cause significant prolongation of the QT interval. These agents should not be used with eliglustat in any patient. Depending on the elimination half-life of concomitant drugs, a considerable waiting period may also be appropriate following their discontinuation before initiating eliglustat. For example, the prolonged duration of CYP450 2D6 inhibition by the moderate CYP450 2D6 inhibitor rolapitant of at least 28 days after its administration should also be taken into account when initiating eliglustat.

GENERALLY AVOID: Grapefruit juice may significantly increase the systemic exposure to eliglustat. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because eliglustat is predicted to cause prolongation of the PR, QTc, and QRS cardiac intervals at substantially elevated plasma concentrations, consumption of grapefruit juice during treatment may increase the risk of bradycardia, atrioventricular block, cardiac arrest, and serious ventricular arrhythmias such as torsade de pointes.

MANAGEMENT: Patients treated with eliglustat should avoid consumption of grapefruit and grapefruit juice.

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.