title: Effect of Hepatic Impairment on the Pharmacokinetics of Pradigastat, a Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor.
abstract: OBJECTIVE
  Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, is under development to treat familial chylomicronemia syndrome. The potential impact of hepatic impairment on the pharmacokinetics of pradigastat was evaluated in this study.
  
  
  METHODS
  In this study, a single oral dose of 20 mg pradigastat was administered first to patients with mild and moderate hepatic impairment (n = 10/group) and subsequently to patients with severe hepatic impairment (n = 6). The pharmacokinetics of pradigastat were compared between each patient group and the respective matched healthy subjects.
  
  
  RESULTS
  As compared with the respective matched healthy groups, the geometric mean ratios of the area under the plasma concentration-time curve from time zero to infinity (AUC inf) (h · ng/mL) were 1.49, 1.06 and 1.99 in mild, moderate and severe hepatic impairment patients, respectively; the observed maximum plasma concentration (C max) (ng/mL) values were 0.97, 1.28 and 2.74, respectively; and the total body clearance of the drug from plasma (CL/F) (L/h) values were 0.67, 0.95 and 0.50, respectively. The elimination half-life and plasma protein binding of pradigastat were comparable among all the patients. There were no apparent relationships between AUC inf or C max and albumin or bilirubin levels (R (2) < 0.3; p > 0.05). Overall, 19 adverse events (AEs) were reported in 13 patients. The incidence of AEs appeared to increase with increasing severity of hepatic impairment.
  
  
  CONCLUSIONS
  No clinically significant differences in the pharmacokinetics of pradigastat were observed in mild and moderate hepatic impairment patients compared with healthy subjects. However, the systemic exposure of pradigastat doubled while the clearance decreased by half in patients with severe hepatic impairment compared with healthy subjects. All treatments were well tolerated in the study.
authors: Novartis Pharma K.K., Tokyo, Japan.
authors: Masaru
authors: M
authors: Hirano
authors: Dan
authors: D
authors: Meyers
authors: GangaRaju
authors: G
authors: Golla
authors: Parasar
authors: P
authors: Pal
authors: Pascale
authors: P
authors: Pinot
authors: TsuHan
authors: T
authors: Lin
authors: Tapan
authors: T
authors: Majumdar
authors: Sam
authors: S
authors: Rebello
authors: Gangadhar
authors: G
authors: Sunkara
authors: Jin
authors: J
authors: Chen
mesh_terms: D000085:Acetates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000631:Aminopyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D015992:Body Mass Index; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D020719:Glucuronides / Q000097:blood; D048550:Hepatic Insufficiency / Q000097:blood / Q000378:metabolism*; D006801:Humans; D008072:Hyperlipoproteinemia Type I / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011485:Protein Binding
chemical_list: D000085:Acetates; D000631:Aminopyridines; D004791:Enzyme Inhibitors; D020719:Glucuronides; C000594809:pradigastat; C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase
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