PMID- 25633714
OWN - NLM
STAT- MEDLINE
DCOM- 20160223
LR  - 20181113
IS  - 1179-1926 (Electronic)
IS  - 0312-5963 (Linking)
VI  - 54
IP  - 7
DP  - 2015 Jul
TI  - Effect of Hepatic Impairment on the Pharmacokinetics of Pradigastat, a 
      Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor.
PG  - 761-70
LID - 10.1007/s40262-015-0235-9 [doi]
AB  - 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.
FAU - Hirano, Masaru
AU  - Hirano M
AD  - Novartis Pharma K.K., Tokyo, Japan.
FAU - Meyers, Dan
AU  - Meyers D
FAU - Golla, GangaRaju
AU  - Golla G
FAU - Pal, Parasar
AU  - Pal P
FAU - Pinot, Pascale
AU  - Pinot P
FAU - Lin, TsuHan
AU  - Lin T
FAU - Majumdar, Tapan
AU  - Majumdar T
FAU - Rebello, Sam
AU  - Rebello S
FAU - Sunkara, Gangadhar
AU  - Sunkara G
FAU - Chen, Jin
AU  - Chen J
LA  - eng
SI  - ClinicalTrials.gov/NCT01594957
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Switzerland
TA  - Clin Pharmacokinet
JT  - Clinical pharmacokinetics
JID - 7606849
RN  - 0 (Acetates)
RN  - 0 (Aminopyridines)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Glucuronides)
RN  - 2U23G6VNUZ (pradigastat)
RN  - EC 2.3.1.20 (DGAT1 protein, human)
RN  - EC 2.3.1.20 (Diacylglycerol O-Acyltransferase)
SB  - IM
MH  - Acetates/administration & dosage/blood/*pharmacokinetics
MH  - Aminopyridines/administration & dosage/blood/*pharmacokinetics
MH  - Body Mass Index
MH  - Diacylglycerol O-Acyltransferase/*antagonists & inhibitors
MH  - Enzyme Inhibitors/administration & dosage/blood/pharmacokinetics
MH  - Female
MH  - Glucuronides/blood
MH  - Hepatic Insufficiency/blood/*metabolism
MH  - Humans
MH  - Hyperlipoproteinemia Type I/blood/drug therapy/metabolism
MH  - Male
MH  - Middle Aged
MH  - Protein Binding
EDAT- 2015/01/31 06:00
MHDA- 2016/02/26 06:00
CRDT- 2015/01/31 06:00
PHST- 2015/01/31 06:00 [entrez]
PHST- 2015/01/31 06:00 [pubmed]
PHST- 2016/02/26 06:00 [medline]
AID - 10.1007/s40262-015-0235-9 [doi]
PST - ppublish
SO  - Clin Pharmacokinet. 2015 Jul;54(7):761-70. doi: 10.1007/s40262-015-0235-9.