Hirano, Masaru, Meyers, Charles, Golla, Ganga Raju, Pal, Parasar, Pinot, Pascale, Lin, Tsu-Han, Majumdar, Tapan, Rebello, Sam, Sunkara, Gangadhar and Chen, Jin (2015) Effect of Hepatic Impairment on the Pharmacokinetics of Pradigastat, a Diacylglycerol Acyltransferase-1 (DGAT1) Inhibitor. Clinical Pharmacokinetics, 54 (7). pp. 761-770. ISSN 0312-5963

Abstract

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 in patients with mild and moderate hepatic impairment (n=10/group) and subsequently to patients with severe hepatic impairment (n=6). The pharmacokinetics of pradigastat for each patient group was compared to the respective matched healthy subjects.
Results
As compared to their respective matched healthy groups, the geometric mean ratios of AUCinf (h•ng/mL) were 1.49, 1.06 and 1.99; Cmax (ng/mL) were 0.97, 1.28 and 2.74, while CL/F (L/h) were 0.67, 0.95 and 0.50 in mild, moderate and severe hepatic impairment patients, respectively. The elimination half-life and plasma protein binding of pradigastat was comparable amongst all the patients. There were no apparent relationships between AUCinf or Cmax and the albumin or bilirubin levels (R2<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 to healthy subjects. However, the systemic exposure of pradigastat doubled while the clearance decreased by half in patients with severe hepatic impairment compared to healthy subjects. All treatments were well tolerated in the study.

Item Type:	Article
Keywords:	Hepatic impairment, pradigastat, pharmacokinetics
Date Deposited:	14 Oct 2016 00:45
Last Modified:	14 Oct 2016 00:45
URI:	https://oak.novartis.com/id/eprint/23357