PMID- 38293761
OWN - NLM
STAT- MEDLINE
DCOM- 20240325
LR  - 20240325
IS  - 1478-3231 (Electronic)
IS  - 1478-3223 (Linking)
VI  - 44
IP  - 4
DP  - 2024 Apr
TI  - Safety, pharmacokinetics and pharmacodynamics of obeticholic acid in subjects 
      with fibrosis or cirrhosis from NASH.
PG  - 966-978
LID - 10.1111/liv.15816 [doi]
AB  - BACKGROUND & AIMS: Fibrosis stage is a strong predictor of nonalcoholic 
      steatohepatitis (NASH) outcomes. Two blinded studies evaluated the 
      pharmacokinetics, pharmacodynamics and safety of obeticholic acid (OCA) in 
      subjects with staged NASH fibrosis or cirrhosis. METHODS: Study 747-117 
      randomized 51 subjects with NASH (fibrosis stages F1-F4) to daily placebo, OCA 10 
      or OCA 25 mg (1:2:2) for 85 days. Study 747-118 randomized 24 subjects with NASH 
      cirrhosis (F4; Child-Pugh [CP]-A) and normal liver control subjects matched for 
      similar body weight to daily OCA 10 or OCA 25 mg (1:1) for 28 days. Individual 
      and combined study data were analysed. RESULTS: No severe or serious adverse 
      events (AEs) or AEs leading to discontinuation or death occurred. Pruritus was 
      the most frequent AE. Plasma OCA exposure (dose-normalized area under the curve) 
      increased with fibrosis stage but was a relatively poor predictor of hepatic OCA 
      exposure (primary site of action), which remained constant across fibrosis stages 
      F1-F3 and increased 1.8-fold compared with F1 in subjects with cirrhosis due to 
      NASH. Both cohorts showed robust changes in farnesoid X receptor activation 
      markers with OCA treatment and marked decreases in alanine transaminase, 
      aspartate transaminase and gamma-glutamyltransferase. CONCLUSIONS: Despite higher 
      drug exposures in subjects with NASH cirrhosis, short-term daily treatment with 
      OCA 10 or 25 mg was generally safe and well tolerated in subjects with NASH 
      fibrosis or NASH CP-A cirrhosis. Both cohorts experienced improvements in 
      nonhistologic pharmacodynamic markers consistent with previously conducted OCA 
      phase 2 and phase 3 studies in NASH fibrosis.
CI  - (c) 2024 Intercept Pharmaceuticals. Liver International published by John Wiley & 
      Sons Ltd.
FAU - Alkhouri, Naim
AU  - Alkhouri N
AUID- ORCID: 0000-0001-9872-2391
AD  - The Texas Liver Institute, University of Texas Health San Antonio, San Antonio, 
      Texas, USA.
AD  - Arizona Liver Health, Chandler, Arizona, USA.
FAU - LaCerte, Carl
AU  - LaCerte C
AD  - Intercept Pharmaceuticals, Inc., San Diego, California, USA.
FAU - Edwards, Jeffrey
AU  - Edwards J
AD  - Intercept Pharmaceuticals, Inc., San Diego, California, USA.
FAU - Poordad, Fred
AU  - Poordad F
AUID- ORCID: 0000-0002-1503-1569
AD  - The Texas Liver Institute, University of Texas Health San Antonio, San Antonio, 
      Texas, USA.
FAU - Lawitz, Eric
AU  - Lawitz E
AUID- ORCID: 0000-0002-4234-224X
AD  - The Texas Liver Institute, University of Texas Health San Antonio, San Antonio, 
      Texas, USA.
FAU - Lee, Lois
AU  - Lee L
AD  - Intercept Pharmaceuticals, Inc., San Diego, California, USA.
FAU - Karan, Sharon
AU  - Karan S
AD  - Intercept Pharmaceuticals, Inc., San Diego, California, USA.
FAU - Sawhney, Sangeeta
AU  - Sawhney S
AD  - Intercept Pharmaceuticals, Inc., Morristown, New Jersey, USA.
FAU - Erickson, Mary
AU  - Erickson M
AD  - Intercept Pharmaceuticals, Inc., San Diego, California, USA.
FAU - MacConell, Leigh
AU  - MacConell L
AD  - Intercept Pharmaceuticals, Inc., San Diego, California, USA.
FAU - Zaru, Luna
AU  - Zaru L
AD  - Intercept Pharmaceuticals, Inc., San Diego, California, USA.
FAU - Chen, Jianfen
AU  - Chen J
AD  - Intercept Pharmaceuticals, Inc., San Diego, California, USA.
FAU - Campagna, Jason
AU  - Campagna J
AD  - Intercept Pharmaceuticals, Inc., San Diego, California, USA.
LA  - eng
GR  - Intercept Pharmaceuticals/
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20240131
PL  - United States
TA  - Liver Int
JT  - Liver international : official journal of the International Association for the 
      Study of the Liver
JID - 101160857
RN  - 0462Z4S4OZ (obeticholic acid)
RN  - 0GEI24LG0J (Chenodeoxycholic Acid)
SB  - IM
MH  - Humans
MH  - *Non-alcoholic Fatty Liver Disease/complications/drug therapy/pathology
MH  - Liver Cirrhosis/drug therapy/pathology
MH  - Chenodeoxycholic Acid/adverse effects/*analogs & derivatives
OTO - NOTNLM
OT  - NASH
OT  - cirrhosis
OT  - fibrosis
OT  - obeticholic acid
OT  - pharmacodynamics
OT  - pharmacokinetics
EDAT- 2024/01/31 06:42
MHDA- 2024/03/25 06:42
CRDT- 2024/01/31 04:38
PHST- 2023/11/13 00:00 [revised]
PHST- 2023/07/19 00:00 [received]
PHST- 2023/11/28 00:00 [accepted]
PHST- 2024/03/25 06:42 [medline]
PHST- 2024/01/31 06:42 [pubmed]
PHST- 2024/01/31 04:38 [entrez]
AID - 10.1111/liv.15816 [doi]
PST - ppublish
SO  - Liver Int. 2024 Apr;44(4):966-978. doi: 10.1111/liv.15816. Epub 2024 Jan 31.