title: Type 1 Gaucher disease (CYP2D6-eliglustat).
abstract: Type 1 Gaucher disease is a rare genetic disease characterized by enzymatic deficit leading to glucosylceramide overload in body tissues (lysosomal overload disease). Standard treatment is based on substitutive enzyme therapy by intravenous perfusion. A new drug for oral administration, eliglustat, was recently awarded marketing approval in Europe and the USA. Eliglustat acts by reducing the enzyme substrate. Eliglustat is mainly eliminated by a CYP2D6 pathway. CYP2D6 exhibits genetic variability or expression, leading to 20-fold differences in serum levels. In marketing approval documents, both the FDA and the EMA mention the requirement for CYP2D6 genotyping before prescribing eliglustat: the drug is contraindicated for ultra-rapid metabolizers (under-dosing inefficacy) and slow metabolizers should be given a 50% reduced daily dose (risk of overdose-related adverse effects). Finally, potential drug interactions (inhibition or induction of CYP2D6 or CYP3A40) are also dependent on CYP2D6 genotyping, such that prescribers must be aware of a patient's genotype before prescribing eliglustat.
authors.affiliation: Inserm, UMR 1184, CEA, DSV/iMETI, division of immuno-virology, IDMIT, pharmacology department, center for immunology of viral infections and autoimmune diseases, hôpital Bicêtre, Assistance publique-Hôpitaux de Paris, faculty of medicine Paris-Sud, university Paris-Sud, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre, France. Electronic address: laurent.becquemont@aphp.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Becquemont
mesh_terms: D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005776:Gaucher Disease / Q000188:drug therapy*; D005838:Genotype; D006801:Humans; D000071185:Pharmacogenomic Testing; D011110:Polymorphism, Genetic; D011759:Pyrrolidines / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D004791:Enzyme Inhibitors; D011759:Pyrrolidines; C522917:eliglustat; D019389:Cytochrome P-450 CYP2D6
keywords: Eliglustat; Gaucher disease; Rare disease