title: Carcinogenicity testing of eliglustat in mice and rats.
abstract: Eliglustat is a novel glucosylceramide synthase inhibitor for long-term oral treatment of type 1 Gaucher disease (GD1), an inherited metabolic disorder. The carcinogenic potential of this drug has been evaluated in lifetime carcinogenicity bioassays in mice and rats. Administration of eliglustat to Swiss CD-1 mice at 0, 10, 25 or 75 mg/kg/day for 104 weeks by dietary admixture did not influence survival or bodyweight evolution, or produce any clinical indication of poor condition. At histopathology, no increases in tumor incidence for any tumor type were attributed to treatment with eliglustat. Systemic exposure to eliglustat was confirmed by a reduction in circulating levels of glucosylceramide. Administration of eliglustat to Sprague-Dawley rats by oral gavage for 105 weeks at 0, 10, 25 or 75 mg/kg/day (males) or 103 weeks at 0, 5, 15 or 50 mg/kg/day (females) did not affect survival rates, but resulted in reduced bodyweight evolution in male rats (-18% at high dose), indicating that the MTD had been achieved. At histopathology, no increases in tumor incidence were attributed to treatment with eliglustat. Systemic exposure was confirmed by toxicokinetic analyses. In conclusion, eliglustat was not carcinogenic to mice or rats in standard lifetime bioassays.
authors.affiliation: Genzyme, Waltham, MA 02451, USA. Electronic address: rdagher@catabasis.com.
authors.forename: Rafif
authors.initials: R
authors.lastname: Dagher
authors.affiliation: CiToxLAB France, 27005 Evreux, France. Electronic address: malene.watzinger@glpg.com.
authors.forename: Malene
authors.initials: M
authors.lastname: Watzinger
authors.affiliation: CiToxLAB France, 27005 Evreux, France. Electronic address: guillaume.chevalier@fr.citoxlab.com.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Chevalier
authors.affiliation: CiToxLAB France, 27005 Evreux, France. Electronic address: catherine.thirion-delalande@fr.citoxlab.com.
authors.forename: Catherine
authors.initials: C
authors.lastname: Thirion-Delalande
authors.affiliation: CiToxLAB France, 27005 Evreux, France. Electronic address: frederic.gervais@fr.citoxlab.com.
authors.forename: Frederic
authors.initials: F
authors.lastname: Gervais
authors.affiliation: CiToxLAB France, 27005 Evreux, France. Electronic address: roy.forster@fr.citoxlab.com.
authors.forename: Roy
authors.initials: R
authors.lastname: Forster
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015197:Carcinogenicity Tests / Q000379:methods; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D005776:Gaucher Disease / Q000188:drug therapy; D008297:Male; D051379:Mice; D009152:Mutagenicity Tests / Q000379:methods; D009369:Neoplasms / Q000139:chemically induced*; D011759:Pyrrolidines / Q000009:adverse effects* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002273:Carcinogens; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; C522917:eliglustat
keywords: Carcinogenicity; Cerdelga; Eliglustat; Gaucher disease; Glucosylceramide synthase inhibitor; Lysosomal storage disease