Pharmacokinetics and Pharmacodynamics of Cilofexor in Adults With Normal and Impaired Hepatic Function

A Phase 1 Open-Label, Parallel-Group, Adaptive, Single-Dose Study to Evaluate the Pharmacokinetics and Pharmacodynamics of GS-9674 in Subjects With Normal and Impaired Hepatic Function

The primary objective of this study is to evaluate the single-dose pharmacokinetics of cilofexor in adults with impaired hepatic function relative to matched, healthy controls with normal hepatic function.

Study Overview

• Status: Completed
• Conditions: Nonalcoholic Steatohepatitis (NASH); Primary Sclerosing Cholangitis (PSC)
• Intervention / Treatment: Drug: Cilofexor

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 1

Contacts and Locations

Study Locations

• New Zealand
  • Auckland, New Zealand, 1640
• United States
  • Florida
    • Miami, Florida, United States, 33014
    • Orlando, Florida, United States, 32809
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
  • Texas
    • San Antonio, Texas, United States, 78215

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

Cohort 1:

• Individuals with mildly impaired and normal hepatic function.
• Individuals with mild hepatic impairment must have a score of 5-6 on the Child-Pugh-Turcotte (CPT) classification at screening without evidence of worsening clinical and/or laboratory signs of hepatic impairment within 2 months prior or within the screening period.

Cohort 2:

• Individuals with moderately impaired and normal hepatic function.
• Individuals with moderate hepatic impairment must have a score of 7-9 on the CPT classification at screening without evidence of worsening clinical and/or laboratory signs of hepatic impairment within 2 months prior or within the screening period.

Cohort 3:

• Individuals with severely impaired and normal hepatic function.
• Individuals with severe hepatic impairment must have a score of 10-15 on the CPT classification at screening without evidence of worsening clinical and/or laboratory signs of hepatic impairment within 2 months prior or within the screening period.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cohort 1: Mild Hepatic Impairment; Participants with mild hepatic impairment will receive a single oral dose of cilofexor 30 mg (3 x 10 mg tablets).	Drug: Cilofexor; Tablet(s) administered orally in a fed state on Day 1; Other Names: GS-9674
EXPERIMENTAL: Cohort 1: Normal Hepatic Function; Matched normal hepatic function participants to mild hepatic impairment participants will receive a single oral dose of cilofexor 30 mg (3 x 10 mg tablets).	Drug: Cilofexor; Tablet(s) administered orally in a fed state on Day 1; Other Names: GS-9674
EXPERIMENTAL: Cohort 2: Moderate Hepatic Impairment; Participants with moderate hepatic impairment will receive a single oral dose of cilofexor 30 mg (3 x 10 mg tablets).	Drug: Cilofexor; Tablet(s) administered orally in a fed state on Day 1; Other Names: GS-9674
EXPERIMENTAL: Cohort 2: Normal Hepatic Function; Matched normal hepatic function participants to moderate hepatic impairment participants will receive a single oral dose of cilofexor 30 mg (3 x 10 mg tablets).	Drug: Cilofexor; Tablet(s) administered orally in a fed state on Day 1; Other Names: GS-9674
EXPERIMENTAL: Cohort 3: Severe Hepatic Impairment; Participants with severe hepatic impairment will receive a single oral dose of cilofexor 10 mg (1 x 10 mg tablet).	Drug: Cilofexor; Tablet(s) administered orally in a fed state on Day 1; Other Names: GS-9674
EXPERIMENTAL: Cohort 3: Normal Hepatic Function; Matched normal hepatic function participants to severe hepatic impairment participants will receive a single oral dose of cilofexor 10 mg (1 x 10 mg tablet).	Drug: Cilofexor; Tablet(s) administered orally in a fed state on Day 1; Other Names: GS-9674

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic (PK) Parameter: AUClast of Cilofexor	AUClast is defined as the concentration of drug from time zero to the last observable concentration.	≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
PK Parameter: AUCinf of Cilofexor	AUCinf is defined as the concentration of drug extrapolated to infinite time.	≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
PK Parameter: Cmax of Cilofexor	Cmax is defined as the maximum concentration of drug.	≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
PK Parameter: %AUCexp of Cilofexor	%AUCexp is defined as the percentage of AUC extrapolated between AUClast and AUCinf.	≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
PK Parameter: Clast of Cilofexor	Clast is defined as the last observable concentration of drug.	≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
PK Parameter: Tmax of Cilofexor	Tmax is defined as the time (observed time point) of Cmax.	≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
PK Parameter: Tlast of Cilofexor	Tlast is defined as the time (observed time point) of Clast.	≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
PK Parameter: λz of Cilofexor	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.	≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
PK Parameter: CL/F of Cilofexor	CL/F is defined as the apparent oral clearance following administration of the drug.	≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
PK Parameter: Vz/F of Cilofexor	Vz/F is defined as the apparent volume of distribution of the drug.	≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
PK Parameter: t1/2 of Cilofexor	t1/2 is defined as the estimate of the terminal elimination half-life of the drug.	≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Experiencing Treatment-Emergent Adverse Events		Day 1 up to Day 31
Percentage of Participants Who Experienced Graded Laboratory Abnormalities	A treatment-emergent laboratory abnormality was defined as an increase of at least 1 toxicity grade from predose at any time postdose up to and including the date of last study drug dose plus 30 days. The most severe graded abnormality from all tests was counted for each participant.	Day 1 up to Day 31
Pharmacodynamic (PD) Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for α-hydroxy-4-cholesten-3-one (C4)	AUC2-12 is defined as area under the curve calculated by the trapezoidal rule for the time from 2 to 12 hours. For PD assessments on Day -1, participants were administered a single oral dose of placebo-to-match cilofexor tablet on Day -1; the reported Time Frame is with respect to the placebo dosing.	0.5 hour predose, ≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, and 16 hours postdose on Day -1 and Day 1; 4.5 hours postdose on Day -1; 24, 48, 72, and 96 hours postdose on Day 1
PD Parameter: Mean Day 1/ Day -1 Ratio of Cmin for α-hydroxy-4-cholesten-3-one (C4)	Cmin for C4 is defined as the minimum observed concentration of C4. For PD assessments on Day -1, participants were administered a single oral dose of placebo-to-match cilofexor tablet on Day -1; the reported Time Frame is with respect to the placebo dosing.	0.5 hour predose, ≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, and 16 hours postdose on Day -1 and Day 1; 4.5 hours postdose on Day -1; 24, 48, 72, and 96 hours postdose on Day 1
PD Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for Fibroblast Growth Factor 19 (FGF19)	AUC2-12 is defined as area under the curve calculated by the trapezoidal rule for the time from 2 to 12 hours. For PD assessments on Day -1, participants were administered a single oral dose of placebo-to-match cilofexor tablet on Day -1; the reported Time Frame is with respect to the placebo dosing.	0.5 hour predose, ≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, and 16 hours postdose on Day -1 and Day 1; 4.5 hours postdose on Day -1; 24, 48, 72, and 96 hours postdose on Day 1
PD Parameter: Mean Day 1/ Day -1 Ratio of Cmax for Fibroblast Growth Factor 19 (FGF19)	Cmax for FGF19 is defined as the maximum observed concentration of FGF19. For PD assessments on Day -1, participants were administered a single oral dose of placebo-to-match cilofexor tablet on Day -1; the reported Time Frame is with respect to the placebo dosing.	0.5 hour predose, ≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, and 16 hours postdose on Day -1 and Day 1; 4.5 hours postdose on Day -1; 24, 48, 72, and 96 hours postdose on Day 1

Collaborators and Investigators

• Sponsor: Gilead Sciences

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 13, 2016
• Primary Completion (ACTUAL): October 16, 2018
• Study Completion (ACTUAL): October 16, 2018

Study Registration Dates

• First Submitted: June 17, 2016
• First Submitted That Met QC Criteria: June 17, 2016
• First Posted (ESTIMATE): June 21, 2016

Study Record Updates

• Last Update Posted (ACTUAL): January 7, 2021
• Last Update Submitted That Met QC Criteria: December 14, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Biliary Tract Diseases; Bile Duct Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Cholangitis; Cholangitis, Sclerosing
• Other Study ID Numbers: GS-US-402-3885

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No