Effect of Hepatic Impairment on the Pharmacokinetics of Pradigastat, a Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor

Clin Pharmacokinet. 2015 Jul;54(7):761-70. doi: 10.1007/s40262-015-0235-9.


Background and 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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT01594957.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / administration & dosage
  • Acetates / blood
  • Acetates / pharmacokinetics*
  • Aminopyridines / administration & dosage
  • Aminopyridines / blood
  • Aminopyridines / pharmacokinetics*
  • Body Mass Index
  • Diacylglycerol O-Acyltransferase / antagonists & inhibitors*
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / blood
  • Enzyme Inhibitors / pharmacokinetics
  • Female
  • Glucuronides / blood
  • Hepatic Insufficiency / blood
  • Hepatic Insufficiency / metabolism*
  • Humans
  • Hyperlipoproteinemia Type I / blood
  • Hyperlipoproteinemia Type I / drug therapy
  • Hyperlipoproteinemia Type I / metabolism
  • Male
  • Middle Aged
  • Protein Binding


  • Acetates
  • Aminopyridines
  • Enzyme Inhibitors
  • Glucuronides
  • pradigastat
  • DGAT1 protein, human
  • Diacylglycerol O-Acyltransferase

Associated data

  • ClinicalTrials.gov/NCT01594957