Modeling and Experimental Studies of Obeticholic Acid Exposure and the Impact of Cirrhosis Stage
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...
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| Published in | Clinical and translational science Vol. 9; no. 6; pp. 328 - 336 |
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| Main Authors | , , , , , , |
| Format | Journal Article |
| Language | English |
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United States
John Wiley & Sons, Inc
01.12.2016
John Wiley and Sons Inc |
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| Online Access | Get full text |
| ISSN | 1752-8054 1752-8062 1752-8062 |
| DOI | 10.1111/cts.12421 |
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| 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). |
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| AbstractList | 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). 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). 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).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). |
| Author | Shapiro, D Gosselin, NH Marier, JF LaCerte, C Peyret, T Edwards, JE Hofmann, AF |
| AuthorAffiliation | 3 Department of Medicine University of California San Diego California USA 2 Certara Strategic Consulting Princeton New Jersey USA 1 Intercept Pharmaceuticals, Inc San Diego California USA |
| AuthorAffiliation_xml | – name: 2 Certara Strategic Consulting Princeton New Jersey USA – name: 1 Intercept Pharmaceuticals, Inc San Diego California USA – name: 3 Department of Medicine University of California San Diego California USA |
| Author_xml | – sequence: 1 givenname: JE surname: Edwards fullname: Edwards, JE email: jeffrey.edwards@interceptpharma.com organization: Intercept Pharmaceuticals, Inc – sequence: 2 givenname: C surname: LaCerte fullname: LaCerte, C organization: Intercept Pharmaceuticals, Inc – sequence: 3 givenname: T surname: Peyret fullname: Peyret, T organization: Certara Strategic Consulting – sequence: 4 givenname: NH surname: Gosselin fullname: Gosselin, NH organization: Certara Strategic Consulting – sequence: 5 givenname: JF surname: Marier fullname: Marier, JF organization: Certara Strategic Consulting – sequence: 6 givenname: AF surname: Hofmann fullname: Hofmann, AF organization: University of California – sequence: 7 givenname: D surname: Shapiro fullname: Shapiro, D organization: Intercept Pharmaceuticals, Inc |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27743502$$D View this record in MEDLINE/PubMed |
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| Copyright | 2016 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics 2016 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics. 2016. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. |
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| SubjectTerms | Acids Adult Area Under Curve Bile Bile acids Chenodeoxycholic Acid - analogs & derivatives Chenodeoxycholic Acid - blood Chenodeoxycholic Acid - pharmacokinetics Chenodeoxycholic Acid - therapeutic use Cirrhosis Computer Simulation Drug dosages Excretion Female Healthy Volunteers Humans Hypertension Intestine Liver Liver cirrhosis Liver Cirrhosis - blood Liver Cirrhosis - drug therapy Liver Cirrhosis - pathology Liver diseases Male Metabolism Models, Biological Pharmaceuticals Plasma levels Reproducibility of Results Studies |
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| Title | Modeling and Experimental Studies of Obeticholic Acid Exposure and the Impact of Cirrhosis Stage |
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