Study to Evaluate the Pharmacokinetics of Firsocostat or Fenofibrate in Adults With Normal and Impaired Hepatic Function

NCT02891408 | Completed Phase 1 Results FDA Drug

• 1 other identifier: GS-US-426-3988
• Study Type: interventional
• Target: 74
• Locations: 1 country
• Sites: 5

Brief Summary

The primary objectives of this study are to evaluate the single-dose pharmacokinetics (PK) of firsocostat in adults with normal hepatic function, and mild, moderate, or severe hepatic impairment and to evaluate the single-dose PK of fenofibrate in adults with normal hepatic function and mild hepatic impairment.

Conditions

Nonalcoholic Steatohepatitis (NASH)

Outcome Measures

Primary Outcomes (11)

• Pharmacokinetic (PK) Parameter: AUClast of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate)

  AUClast is defined as the concentration of drug from time zero to the last observable concentration. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).

  Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable)

• PK Parameter: AUCinf of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate)

  AUCinf is defined as the concentration of drug extrapolated to infinite time. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).

  Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable)

• PK Parameter: Cmax of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate)

  Cmax is defined as the maximum observed concentration of drug. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).

  Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable)

• PK Parameter: % AUCexp of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate)

  %AUCexp is defined as the percentage of AUC extrapolated between AUClast and AUCinf. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).

  Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable)

• PK Parameter: Tmax of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate)

  Tmax is defined as the time (observed time point) of Cmax. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).

  Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable)

• PK Parameter: Clast of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate)

  Clast is defined as the last observed quantifiable concentration of drug. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).

  Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable)

• PK Parameter: Tlast of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate)

  Tlast is defined as the time (observed time point) of Clast. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).

  Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable)

• PK Parameter: λz of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate)

  λz is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log plasma concentration of drug versus time curve of the drug. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).

  Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable)

• PK Parameter: CL/F of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate)

  CL/F is defined as the apparent oral clearance following administration of the drug. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).

  Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable)

• PK Parameter: Vz/F of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate)

  Vz/F is defined as the apparent volume of distribution of the drug. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).

  Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable)

• PK Parameter: t1/2 of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate)

  t1/2 is defined as the estimate of the terminal elimination half-life of the drug. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).

  Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable)

Secondary Outcomes (2)

• Percentage of Participants Experiencing Treatment-Emergent Adverse Events (AEs)

  First dose date plus 30 days

• Percentage of Participants Experiencing Laboratory Abnormalities

  First dose date plus 30 days

Study Arms (8)

Cohort 1 (Mild Hepatic Impairment): Firsocostat 20 mg

EXPERIMENTAL

Participants with mild hepatic impairment will receive a single dose of firsocostat 20 mg (2 × 10 mg capsules).

Drug: Firsocostat

Cohort 1 (Normal Hepatic Function): Firsocostat 20 mg

EXPERIMENTAL

Matched normal hepatic function participants to mild hepatic impairment participants will receive a single dose of firsocostat 20 mg (2 × 10 mg capsules).

Drug: Firsocostat

Cohort 2 (Moderate Hepatic Impairment): Firsocostat 20 mg

EXPERIMENTAL

Participants with moderate hepatic impairment will receive a single dose of firsocostat 20 mg (2 × 10 mg capsules).

Drug: Firsocostat

Cohort 2 (Normal Hepatic Function): Firsocostat 20 mg

EXPERIMENTAL

Matched normal hepatic function participants to moderate hepatic impairment participants will receive a single dose of firsocostat 20 mg (2 × 10 mg capsules).

Drug: Firsocostat

Cohort 3 (Severe Hepatic Impairment): Firsocostat 5 mg

EXPERIMENTAL

Participants with severe hepatic impairment will receive a single dose of firsocostat 5 mg (1 × 5 mg capsule).

Drug: Firsocostat

Cohort 3 (Normal Hepatic Function) Firsocostat 5 mg

EXPERIMENTAL

Matched normal hepatic function participants to severe hepatic impairment participants will receive a single dose of firsocostat 5 mg (1 × 5 mg capsule).

Drug: Firsocostat

Cohort 4 (Mild Hepatic Impairment): Fenofibrate 48 mg

EXPERIMENTAL

Participants with mild hepatic impairment will receive a single dose of fenofibrate 48 mg (1 × 48 mg tablet).

Drug: Fenofibrate

Cohort 4 (Normal Hepatic Function) Fenofibrate 48 mg

EXPERIMENTAL

Matched normal hepatic function participants to mild hepatic impairment participants, will receive a single dose of fenofibrate 48 mg (1 × 48 mg tablet).

Drug: Fenofibrate

Interventions

Firsocostat DRUG

Capsule(s) administered orally on Day 1

Also known as: GS-0976

Cohort 1 (Mild Hepatic Impairment): Firsocostat 20 mg; Cohort 1 (Normal Hepatic Function): Firsocostat 20 mg; Cohort 2 (Moderate Hepatic Impairment): Firsocostat 20 mg; Cohort 2 (Normal Hepatic Function): Firsocostat 20 mg; Cohort 3 (Normal Hepatic Function) Firsocostat 5 mg; Cohort 3 (Severe Hepatic Impairment): Firsocostat 5 mg

Fenofibrate DRUG

Tablet administered orally on Day 1

Cohort 4 (Mild Hepatic Impairment): Fenofibrate 48 mg; Cohort 4 (Normal Hepatic Function) Fenofibrate 48 mg

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Cohort 1 (Mild Hepatic Impairment):
• Male and non-pregnant/non-lactating females with mildly impaired and normal hepatic function.
• Individuals will be current non-smokers (no use of tobacco, nicotine-containing or tetrahydrocannabinol (THC)-containing products within the last 14 days).
• Each individual in the control group will be matched for age (± 10 years), gender, race, and body mass index (± 15% 18 ≤ body mass index (BMI) ≤ 36 kg/m\^2) with an individual in the mild hepatic impairment group.
• Individuals with mild hepatic impairment must have a score of 5-6 on the Child-Pugh-Turcotte (CPT) Classification at screening, have diagnosis of chronic (\> 6 months), and stable hepatic impairment with no clinically significant changes within 3 months (or 90 days) prior to study drug administration (Day 1).
• Cohort 2 (Moderate Hepatic Impairment):
• Male and non-pregnant/non-lactating females with moderately impaired and normal hepatic function.
• Individuals will be current non-smokers (no smoking of tobacco, nicotine-containing or THC-containing products within the last 14 days).
• Each individual in the control group will be matched for age (± 10 years), gender, race, and body mass index (± 15% 18 ≤ BMI ≤ 36 kg/m\^2) with an individual in the moderate hepatic impairment group.
• Individuals with moderate hepatic impairment must have a score of 7-9 on the CPT Classification at screening, have diagnosis of chronic (\> 6 months), and stable hepatic impairment with no clinically significant changes within 3 months (or 90 days) prior to study drug administration (Day 1).
• Cohort 3 (Severe Hepatic Impairment):
• Male and nonpregnant/non-lactating females with severely impaired and normal hepatic function.
• Individuals will be current non-smokers (no use of tobacco, nicotine-containing or THC-containing products within the last 14 days).
• Each individual in the control group will be matched for age (± 10 years), gender, race, and body mass index (± 15% 18 ≤ BMI ≤ 36 kg/m\^2) with an individual in the severe hepatic impairment group.
• Individuals with severe hepatic impairment must have a score of 10-15 on the CPT Classification at screening, have diagnosis of chronic (\> 6 months), and stable hepatic impairment with no clinically significant changes within 3 months (or 90 days) prior to study drug administration (Day 1).

Sponsors & Collaborators

• Gilead Sciences: lead

Study Sites (5)

Unknown Facility

Tustin, California, United States

Location

Unknown Facility

Miami, Florida, United States

Location

Unknown Facility

Orlando, Florida, United States

Location

Unknown Facility

Minneapolis, Minnesota, United States

Location

Unknown Facility

San Antonio, Texas, United States

Location

Related Publications (1)

• Nelson C, Weber E, Yue MS, Millward V, Qin AR, Marbury TC, et al. The Pharmacokinetics of GS-0976, an Acetyl-CoA Carboxylase (ACC) Inhibitor, in Subjects with Mild, Moderate, and Severe Hepatic Impairment [Abstract 1719]. Hepatology AASLD Abstracts 2018;68 (Suppl 1):979A-80A.

  RESULT

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease

Interventions

firsocostat; Fenofibrate

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Fibric Acids; Isobutyrates; Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Phenyl Ethers; Ethers; Benzophenones; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phenols; Ketones

Results Point of Contact

• Title: Gilead Clinical Study Information Center
• Organization: Gilead Sciences

GileadClinicalTrials@gilead.com

1-833-445-3230 (GILEAD-0)

Study Officials

• Gilead Study Director

  Gilead Sciences

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 1, 2016
• First Posted: September 7, 2016
• Study Start: September 23, 2016
• Primary Completion: May 5, 2019
• Study Completion: May 13, 2019
• Last Updated: December 17, 2020
• Results First Posted: December 17, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)