title: Safety, tolerability, and pharmacokinetics of eliglustat tartrate (Genz-112638) after single doses, multiple doses, and food in healthy volunteers.
abstract: Three phase 1 studies of eliglustat tartrate (Genz-112638), an oral inhibitor of glucosylceramide synthase under development for treating Gaucher disease type 1 (GD1), evaluated the safety, tolerability, and pharmacokinetics in healthy volunteers after escalating single doses (n = 99), escalating multiple doses (n = 36), and food (n = 24). Eliglustat tartrate was well tolerated at single doses ≤ 20 mg/kg and multiple doses ≤ 200 mg bid, with 50 mg bid producing plasma concentrations in the predicted therapeutic range. No serious adverse events occurred. Mild to moderate events of nausea, dizziness, and vomiting increased in frequency with escalating single and multiple doses. Single doses ≥ 10 mg/kg caused mild increases in electrocardiogram PR, QRS, and QT/QTc intervals. Single-dose pharmacokinetics showed dose linearity but not proportionality. Maximum plasma concentrations occurred at ~2 hours, followed by a monophasic decline with a ~6-hour terminal half-life. Unchanged drug in 8-hour urine collections was <1.5% of administered doses. Food did not significantly affect the rate or extent of absorption. Multiple-dose pharmacokinetics was nonlinear, showing higher than expected plasma drug concentrations. Steady state was reached ~60 hours after bid dosing. Higher drug exposure occurred in slower CYP2D6 metabolizers. Based on favorable results in healthy participants, a phase 2 trial of eliglustat tartrate was initiated in GD1 patients.
authors.affiliation: Genzyme Corporation, 500 Kendall Street, Cambridge, MA 02142, USA. judith.peterschmitt@genzyme.com
authors.forename: M Judith
authors.initials: MJ
authors.lastname: Peterschmitt
authors.forename: Amy
authors.initials: A
authors.lastname: Burke
authors.forename: Larry
authors.initials: L
authors.lastname: Blankstein
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Smith
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Puga
authors.forename: William G
authors.initials: WG
authors.lastname: Kramer
authors.forename: James A
authors.initials: JA
authors.lastname: Harris
authors.forename: David
authors.initials: D
authors.lastname: Mathews
authors.forename: Peter L
authors.initials: PL
authors.lastname: Bonate
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001711:Biotransformation; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D004244:Dizziness / Q000139:chemically induced; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005260:Female; D018565:Food-Drug Interactions; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D008954:Models, Biological; D009325:Nausea / Q000139:chemically induced; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D014839:Vomiting / Q000139:chemically induced; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D011759:Pyrrolidines; C522917:eliglustat; D019389:Cytochrome P-450 CYP2D6; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase