Drug Interactions between eliglustat and osilodrostat

GENERALLY AVOID: Coadministration with weak inhibitors of CYP450 3A4 may 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 potent CYP450 3A4 inhibitor ketoconazole may increase eliglustat systemic exposure (AUC) by 4.4-, 5.4- and 6.2-fold in CYP450 2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs), respectively, while the moderate CYP450 3A4 inhibitor fluconazole may increase eliglustat AUC by 3.2-, 2.9- and 3.0-fold, respectively. No data are available for use with other, less potent inhibitors.

MANAGEMENT: Concomitant use of eliglustat with weak CYP450 3A4 inhibitors such as chloramphenicol, cyclosporine, danazol, dasatinib, ethinyl estradiol, fluvoxamine, goldenseal, isoniazid, ivacaftor, lapatinib, lomitapide, nifedipine, nilotinib, palbociclib, pazopanib, suvorexant, ticagrelor, and zafirlukast is not recommended in CYP450 2D6 poor metabolizers. No dosage adjustment for eliglustat is necessary when used with weak CYP450 3A4 inhibitors in extensive or intermediate metabolizers.