Eliglustat 84mg capsules

Eliglustat administered in multiple doses of 84 mg twice daily had a C_max of 12.1 to 25.0 ng/mL in CYP2D6 extensive metabolizers (EMs), 44.6 ng/mL in CYP2D6 intermediate metabolizers (IMs), and 113 to 137 ng/mL in CYP2D6 poor metabolizers (PMs).
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The median T_max was 1.5-2 hr in CYP2D6 EMs, 2 hr in CYP2D6 IMs, and 3 hr in CYP2D6 PMs.
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The AUC_tau was 76.3-143 ng∙hr/mL in CYP2D6 EMs, 306 ng∙hr/mL in CYP2D6 IMs, and 922-1057 ng∙hr/mL in CYP2D6 PMs.
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In CYP2D6 EMs, the pharmacokinetics of eliglustat is time-dependent, and for doses that range between 42 and 294 mg, exposure increases in a more than dose-proportional fashion. In CYP2D6 PMs, eliglustat pharmacokinetics is linear and time-independent. In a steady state, the systemic exposure of 84 mg eliglustat twice daily is 7- to 9-fold higher in CYP2D6 PMs compared to EMs.
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Following the oral administration of a single 84 mg dose of eliglustat, bioavailability in CYP2D6 EMs was lower than 5%.
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The low oral bioavailability of eliglustat suggests the role of transporters and/or an extensive first-pass metabolism.
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Eliglustat can be taken with or without food.
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In CYP2D6 EMs, severe renal impairment did not have an effect on eliglustat pharmacokinetics.

The effect of renal impairment on eliglustat pharmacokinetics was not evaluated in CYP2D6 IMs, CYP2D6 PMs or CYP2D6 EMs with end-stage renal failure.
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Compared to CYP2D6 EMs with normal hepatic function, C_max and AUC were 1.2-fold higher in CYP2D6 EMs with mild hepatic impairment, while C_max and AUC were 2.8- and 5.2-fold higher, respectively, in CYP2D6 EMs with moderate hepatic impairment. The effect of mild and moderate hepatic impairment in CYP2D6 IMs and PMs, and the effect of severe hepatic impairment were not evaluated.
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Eliglustat is mostly metabolized by CYP2D6, and to a lower extent, by CYP3A4.
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In patients that are CYP2D6 poor metabolizers (PMs), eliglustat is mainly metabolized by CYP3A4. The primary metabolic pathways of eliglustat involve the sequential oxidation of the octanoyl moiety and the 2,3-dihydro-1,4-benzodioxane moiety. The combination of these two pathways results in the production of several oxidative metabolites.
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After evaluating the potency of eliglustat metabolites, it was determined that none of them were active.
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Genz-399240 (M24) was identified as the major metabolite of eliglustat, while the rest of the metabolites contributed to less than 10% of total drug-related exposures.
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Genz-399240 (M24) did not show any major off-target effects; therefore, a transporter substrate specificity characterization was not performed.
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