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

Nonalcoholic Steatohepatitis (NASH) Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02808312
• Other study ID #: GS-US-402-3885
• Status: Completed
• Phase: Phase 1
• Start date: July 13, 2016
• Est. completion date: October 16, 2018

Study information

• Verified date: December 2020
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 57
• Est. completion date: October 16, 2018
• Est. primary completion date: October 16, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cholangitis
• Cholangitis, Sclerosing
• Fatty Liver
• Non-alcoholic Fatty Liver Disease
• Nonalcoholic Steatohepatitis (NASH)
• Primary Sclerosing Cholangitis (PSC)

Intervention

Drug:
• Cilofexor
Tablet(s) administered orally in a fed state on Day 1

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  New Zealand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	PK Parameter: ?z of Cilofexor	?z 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
Primary	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
Primary	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
Primary	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	Percentage of Participants Experiencing Treatment-Emergent Adverse Events		Day 1 up to Day 31
Secondary	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
Secondary	Pharmacodynamic (PD) Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for a-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
Secondary	PD Parameter: Mean Day 1/ Day -1 Ratio of Cmin for a-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
Secondary	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
Secondary	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