Impact of hepatic and renal impairment on the pharmacokinetics and tolerability of eliglustat therapy for Gaucher disease type 1

https://doi.org/10.1016/j.ymgme.2019.11.002Get rights and content
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Highlights

  • Mild hepatic or severe renal impairment did not affect eliglustat exposure in CYP2D6 extensive metabolizers.

  • Moderate hepatic impairment increased eliglustat exposure in CYP2D6 extensive metabolizers.

  • CYP2D6/CYP3A inhibitors may increase eliglustat exposure in CYP2D6 extensive metabolizers with moderate hepatic impairment.

  • These studies did not provide definitive conclusions regarding CYP2D6 intermediate and poor metabolizers.

  • The eliglustat label was updated with recommendations and contraindications for patients with hepatic or renal impairment.

Abstract

Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) who have extensive (EM), intermediate (IM), or poor (PM) CYP2D6 metabolizer phenotypes. It was initially not recommended in GD1 patients with hepatic or renal impairment due to insufficient data. Two Phase 1 studies (NCT02536937/NCT02536911) evaluated the effects of hepatic and renal impairment on pharmacokinetics and tolerability following a single 84-mg dose of eliglustat. Compared to matched healthy EM subjects (n = 7 for both studies), geometric means for eliglustat maximum concentration (Cmax) and area under the plasma concentration versus time curve extrapolated to infinity (AUC) were not substantially different in EMs with mild hepatic impairment (n = 6), higher in EMs with moderate hepatic impairment (n = 7), and similar in EMs with severe renal impairment (n = 7). Higher exposures of eliglustat at steady-state were predicted using a physiologically-based pharmacokinetic (PBPK) model in EMs with mild or moderate hepatic impairment compared with normal hepatic function after repeated 84-mg eliglustat doses. Higher exposures of eliglustat were also predicted in EMs with mild hepatic impairment after coadministration with a CYP2D6 or CYP3A inhibitor with repeated doses. Based on these results, the eliglustat drug label was revised for patients with hepatic or renal impairment.

Cited by (0)

1

Current affiliation: Alkermes, Inc. Waltham, MA, USA.

2

Current affiliation: Amgen, Thousand Oaks, CA, USA.

3

Current affiliation: Sperogenix Therapeutics, Shanghai, China.

4

Current affiliation: Global Blood Therapeutics, South San Francisco, CA, USA.