Drug Interactions between atazanavir / cobicistat and eliglustat

CONTRAINDICATED: Coadministration with moderate inhibitors of CYP450 3A4 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. Simulations using physiologically-based pharmacokinetic (PBPK) models suggest that the moderate CYP450 3A4 inhibitor fluconazole may increase eliglustat peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.8- and 3.2-fold, respectively, in CYP450 2D6 extensive metabolizers (EMs) given eliglustat 84 mg twice daily, and 2.5- and 2.9-fold, respectively, in intermediate metabolizers (IMs) given the same dosage. PBPK modeling also suggest that fluconazole may increase eliglustat Cmax by 2.4-fold and AUC by 3.0-fold in poor metabolizers (PMs) given eliglustat 84 mg once daily. The magnitude of interaction is expected to increase further with the addition of a CYP450 2D6 inhibitor like terbinafine. Simulations using PBPK models 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 inhibition of CYP450 3A4 and moderate to potent inhibition of CYP450 2D6 is considered contraindicated in CYP450 2D6 extensive metabolizers (EMs) and intermediate metabolizers (IMs). In the absence of a concomitant CYP450 2D6 inhibitor, eliglustat may be prescribed at a reduced dosage of 84 mg once daily to EMs treated with a moderate CYP450 3A4 inhibitor. However, eliglustat should not be used with a moderate CYP450 3A4 inhibitor in CYP450 2D6 IMs or poor metabolizers (PMs). Moderate CYP450 3A4 inhibitors include aprepitant, ciprofloxacin, clotrimazole, crizotinib, darunavir, diltiazem, dronedarone, fluconazole, fusidic acid, imatinib, isavuconazonium, miconazole, mifepristone, netupitant, quinupristin-dalfopristin, ranolazine, stiripentol, and verapamil. Potent and moderate CYP450 2D6 inhibitors include abiraterone, bupropion, celecoxib, cimetidine, cinacalcet, clobazam, darifenacin, diphenhydramine, duloxetine, fluoxetine, methotrimeprazine, mirabegron, paroxetine, propoxyphene, quinidine, ranolazine, sertraline, stiripentol, and terbinafine.

CONTRAINDICATED: Coadministration with potent inhibitors of CYP450 3A4 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 31 subjects who were CYP450 2D6 extensive metabolizers (EMs), eliglustat peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 4.0- and 4.4-fold, respectively, following coadministration of eliglustat (84 mg twice daily) with the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily). Simulations using physiologically-based pharmacokinetic (PBPK) models suggest that ketoconazole may increase eliglustat Cmax by 4.4-fold and AUC by 5.4-fold in CYP450 2D6 intermediate metabolizers (IMs). PBPK modeling also suggest that ketoconazole may increase eliglustat Cmax by 4.3-fold and AUC by 6.2-fold in CYP450 2D6 poor metabolizers (PMs) given eliglustat 84 mg once daily (half the dosage used in EMs). The magnitude of interaction is expected to increase further with the addition of a CYP450 2D6 inhibitor like paroxetine. Simulations using PBPK models suggest that the combination of ketoconazole (400 mg once daily) and paroxetine (30 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.

MANAGEMENT: The use of eliglustat with a potent CYP450 3A4 inhibitor is considered contraindicated in CYP450 2D6 poor metabolizers (PMs) and intermediate metabolizers (IMs). The contraindication is extended to extensive metabolizers (EMs) when a moderate or potent CYP450 2D6 inhibitor is given concomitantly with a moderate or potent CYP450 3A4 inhibitor. In the absence of a concomitant CYP450 2D6 inhibitor, eliglustat may be prescribed at a reduced dosage of 84 mg once daily to EMs treated with a potent CYP450 3A4 inhibitor. Potent CYP450 3A4 inhibitors include itraconazole, ketoconazole, posaconazole, voriconazole, conivaptan, ceritinib, idelalisib, mibefradil, nefazodone, cobicistat, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics. Potent and moderate CYP450 2D6 inhibitors include abiraterone, bupropion, celecoxib, cimetidine, cinacalcet, clobazam, darifenacin, diphenhydramine, dronedarone, duloxetine, flecainide, fluoxetine, methotrimeprazine, mirabegron, paroxetine, propafenone, propoxyphene, quinidine, ranolazine, sertraline, and terbinafine. Some drugs such as cobicistat, delavirdine, mibefradil, adagrasib and ritonavir are dual CYP450 3A4 and 2D6 inhibitors, and they should not be used with eliglustat in any patient regardless of their CYP450 2D6 metabolizer status. The product labeling for itraconazole states that concomitant use with eliglustat is contraindicated in CYP450 2D6 EMs taking a strong or moderate CYP450 2D6 inhibitor, CYP450 2D6 IMs and PMs during and for 2 weeks after treatment with itraconazole.