Hepatic Impairment Trial of Obeticholic Acid

Study Overview
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Brief Summary
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This is a phase 1 study to evaluate the safety of a single 10 mg dose of obeticholic acid (OCA) in healthy volunteers and patients with liver disease.

Official Title
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An Open-Label, Single-Dose Trial to Assess the Effects of Hepatic Impairment on the Pharmacokinetics of Obeticholic Acid (OCA)

Conditions
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Hepatic Impairment

Intervention / Treatment
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* Drug: obeticholic acid 10 mg


Participation Criteria
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Eligibility Criteria
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Subject Inclusion Criteria All Subjects Female and male subjects ≥ 18 years of age Subjects will have a minimum body weight of 45 kg or body mass index (BMI)> 18 kg/m2. Contraception: Female subjects must be postmenopausal, surgically sterile, or if premenopausal, be prepared to use ≥ 1 effective method of contraception during the trial and until at least 30 days after administration of OCA. Subjects must provide written informed consent and agree to comply with the trial protocol. Subjects with Hepatic Impairment: Evidence of hepatic disease Score ≥ 2 on one of the Child-Pugh parameters, or Histological diagnosis of cirrhosis or presence of esophageal varices, or Abnormal alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) levels Subjects will satisfy the criteria of the modified Child-Pugh classification for hepatic impairment during Screening: Mild hepatic impairment: Class A (Child-Pugh Scores 5-6 points) Moderate hepatic impairment: Class B (Child-Pugh Scores 7-9 points) Severe hepatic impairment: Class C (Child Pugh Scores 10-15 points) Healthy volunteers: Absence of clinically-relevant abnormalities identified by a detailed medical history, full physical examination, 12-lead ECG Clinical laboratory tests within the normal reference range Subjects must be within ± 10 years of the mean age and within 20% of the mean BMI of the hepatic impaired subjects (Child-Pugh category A, B, and C) Subject Exclusion Criteria All Subjects Positive test for human immunodeficiency virus (HIV)-1 or HIV-2 at screening Presence or history of malignancy, with the exception of basal cell carcinoma Received an investigational drug, including OCA, within 30 days or t½=5 prior to dosing Blood or plasma donation within 30 days prior to dosing History of non-compliance to medical regimens, or subjects who are considered to be potentially unreliable Presence or history of clinically significant cardiac arrhythmias that may prohibit the subject from participating in the trial Female subjects who are pregnant or lactating Subjects who have irritable bowel disease or other GI disorders that have the potential to alter drug or bile acid absorption. Subjects who have a history of gall bladder removal, gastric bypass or other GI surgery that may affect drug absorption or the enterohepatic circulation. Subjects with Hepatic Impairment History of alcohol or drug abuse 3 months prior to dosing In the opinion of the Investigator and medical monitor, fluctuating or rapidly deteriorating hepatic function within the screening period In the opinion of the Investigator, any evidence of additional severe or uncontrolled systemic disease or evidence of any other significant clinical disorder or laboratory finding likely to affect the conduct of the trial or interpretation of the data Subjects who have a transjugular intrahepatic portosystemic shunt and/or have undergone portacaval shunting Subjects with Wilson's disease, alpha-1 antitrypsin deficiency, glycogen storage diseases and galactosemia Heavy smoker or use of tobacco or nicotine products Healthy Volunteers Presence of significant uncontrolled disease that will complicate execution of the trial or interfere with the absorption, distribution, metabolism, or excretion of drugs via the gut Evidence of chronic or acute liver disease as documented by medical history, physical examination or diagnostic tests that it likely to affect the conduct of the trial or interpretation of the data History of and/or current alcohol abuse (defined as consumption of more than 210 mL of alcohol per week; or the equivalent of fourteen 4-oz glasses of wine, or fourteen 12-oz cans/bottles of beer or wine coolers per week) or drug abuse within the prior two years Smoke or use tobacco or nicotine products

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy Volunteer<br>Healthy volunteers receiving a single dose of obeticholic acid 10 mg. | Drug: obeticholic acid 10 mg<br>* Single dose OCA 10mg in each arm<br>* Other names: 6-ECDCA;|
| Experimental: Mild Hepatic Impairment<br>Subjects with mild hepatic impairment defined as Child-Pugh class A receiving a single dose of obeticholic acid 10mg. | Drug: obeticholic acid 10 mg<br>* Single dose OCA 10mg in each arm<br>* Other names: 6-ECDCA;|
| Experimental: Moderate Hepatic Impairment<br>Subjects with moderate hepatic impairment defined as Child-Pugh class B receiving obeticholic acid 10mg. | Drug: obeticholic acid 10 mg<br>* Single dose OCA 10mg in each arm<br>* Other names: 6-ECDCA;|
| Experimental: Severe Hepatic Impairment<br>Subjects with severe hepatic impairment defined as Child-Pugh class C receiving obeticholic acid 10 mg. | Drug: obeticholic acid 10 mg<br>* Single dose OCA 10mg in each arm<br>* Other names: 6-ECDCA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak plasma concentration (Cmax) of OCA and conjugates | maximum concentration | Up to 48 hours | 
| Area under the concentration versus time curve from time 0 to the last sampling time with measurable analyte concentration (AUCt) of OCA and conjugates |  | Post-dose 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, and 216 hours post-dose | 
| Time to Cmax (Tmax) of OCA and conjugates |  | Up to 48 hours | 
| Area under the concentration versus time curve from time 0-24 hours with measurable analyte concentration of OCA and conjugates. (AUC 0-24) |  | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urine concentration of unchanged OCA and conjugates |  | 0, 6, 12, 24, 30 hours | 
| Amount of OCA and conjugates excretion in urine |  | -6to 0, 0 to 6, 6 to 12, 12 to 24, and 24 to 30 hours | 
| Total amount of OCA and conjugates excreted in urine |  | 0 to 30 hours | 
| Protein Binding |  | 0, 0.75, 1.5, 6, and 24 hours |