Drug Interactions between Agenerase 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.