title: Modeling and Experimental Studies of Obeticholic Acid Exposure and the Impact of Cirrhosis Stage.
abstract: Obeticholic acid (OCA), a semisynthetic bile acid, is a selective and potent farnesoid X receptor (FXR) agonist in development for the treatment of chronic nonviral liver diseases. Physiologic pharmacokinetic models have been previously used to describe the absorption, distribution, metabolism, and excretion (ADME) of bile acids. OCA plasma levels were measured in healthy volunteers and cirrhotic subjects. A physiologic pharmacokinetic model was developed to quantitatively describe the ADME of OCA in patients with and without hepatic impairment. There was good agreement between predicted and observed increases in systemic OCA exposure in subjects with mild, moderate, and severe hepatic impairment, which were 1.4-, 8-, and 13-fold relative to healthy volunteers. Predicted liver exposure for subjects with mild, moderate, and severe hepatic impairment were increased only 1.1-, 1.5-, and 1.7-fold. In subjects with cirrhosis, OCA exposure in the liver, the primary site of pharmacological activity along with the intestine, is increased marginally (∼2-fold).
authors.affiliation: Intercept Pharmaceuticals, Inc, San Diego, California, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Edwards
authors.affiliation: Intercept Pharmaceuticals, Inc, San Diego, California, USA.
authors.forename: C
authors.initials: C
authors.lastname: LaCerte
authors.affiliation: Certara Strategic Consulting, Princeton, New Jersey, USA.
authors.forename: T
authors.initials: T
authors.lastname: Peyret
authors.affiliation: Certara Strategic Consulting, Princeton, New Jersey, USA.
authors.forename: N H
authors.initials: NH
authors.lastname: Gosselin
authors.affiliation: Certara Strategic Consulting, Princeton, New Jersey, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Marier
authors.affiliation: Department of Medicine, University of California, San Diego, California, USA.
authors.forename: A F
authors.initials: AF
authors.lastname: Hofmann
authors.affiliation: Intercept Pharmaceuticals, Inc, San Diego, California, USA.
authors.forename: D
authors.initials: D
authors.lastname: Shapiro
mesh_terms: D000328:Adult; D019540:Area Under Curve; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D003198:Computer Simulation; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008099:Liver; D008103:Liver Cirrhosis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008954:Models, Biological; D015203:Reproducibility of Results
chemical_list: C464660:obeticholic acid; D002635:Chenodeoxycholic Acid