Nonalcoholic Steatohepatitis (NASH), Primary Sclerosing Cholangitis (PSC)
Conditions
Brief 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.
Interventions
DRUGCilofexor
Tablet(s) administered orally in a fed state on Day 1
Sponsors
Gilead Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PK Parameter: t1/2 of Cilofexor | ≤ 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 | t1/2 is defined as the estimate of the terminal elimination half-life of the drug. |
| PK Parameter: Cmax of Cilofexor | ≤ 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 | Cmax is defined as the maximum concentration of drug. |
| PK Parameter: %AUCexp of Cilofexor | ≤ 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 | %AUCexp is defined as the percentage of AUC extrapolated between AUClast and AUCinf. |
| PK Parameter: Tlast of Cilofexor | ≤ 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 | Tlast is defined as the time (observed time point) of Clast. |
| PK Parameter: λz of Cilofexor | ≤ 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 | 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. |
| PK Parameter: CL/F of Cilofexor | ≤ 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 | CL/F is defined as the apparent oral clearance following administration of the drug. |
| PK Parameter: Vz/F of Cilofexor | ≤ 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 | Vz/F is defined as the apparent volume of distribution of the drug. |
| PK Parameter: Tmax of Cilofexor | ≤ 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 | Tmax is defined as the time (observed time point) of Cmax. |
| PK Parameter: Clast of Cilofexor | ≤ 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 | Clast is defined as the last observable concentration of drug. |
| Pharmacokinetic (PK) Parameter: AUClast of Cilofexor | ≤ 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 | AUClast is defined as the concentration of drug from time zero to the last observable concentration. |
| PK Parameter: AUCinf of Cilofexor | ≤ 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 | AUCinf is defined as the concentration of drug extrapolated to infinite time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Day 1 up to Day 31 | 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. |
| Pharmacodynamic (PD) Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for α-hydroxy-4-cholesten-3-one (C4) | 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 | 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. |
| PD Parameter: Mean Day 1/ Day -1 Ratio of Cmin for α-hydroxy-4-cholesten-3-one (C4) | 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 | 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. |
| PD Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for Fibroblast Growth Factor 19 (FGF19) | 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 | 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. |
| PD Parameter: Mean Day 1/ Day -1 Ratio of Cmax for Fibroblast Growth Factor 19 (FGF19) | 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 | 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. |
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events | Day 1 up to Day 31 | — |
Countries
New Zealand, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States (US) and New Zealand. The first participant was screened on 13 July 2016. The last study visit occurred on 16 October 2018.
Pre-assignment details
In the control groups (normal hepatic function), each participant was matched for age, gender, race, and body mass index with a participant in the hepatic impairment group. 17 total unique participants with normal hepatic function were enrolled in Cohort 1 (N = 10) and Cohort 2 (N = 7). 5 participants with normal hepatic function from Cohort 1 also served as matched controls in Cohort 2.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Mild Hepatic Impairment Participants with mild hepatic impairment received a single oral dose of cilofexor 30 mg (3 x 10 mg tablets) in a fed state, on Day 1. | 10 |
| Cohort 2: Moderate Hepatic Impairment Participants with moderate hepatic impairment received a single oral dose of cilofexor 30 mg (3 x 10 mg tablets) in a fed state, on Day 1. | 10 |
| Cohort 1 & 2: Normal Hepatic Function Matched normal hepatic function participants to mild or moderate hepatic impairment participants, received a single oral dose of cilofexor 30 mg (3 x 10 mg tablets) in a fed state, on Day 1. | 16 |
| Cohort 3: Severe Hepatic Impairment Participants with severe hepatic impairment received a single oral dose of cilofexor 10 mg (1 x 10 mg tablet) in a fed state, on Day 1. | 10 |
| Cohort 3: Normal Hepatic Function Matched normal hepatic function participants, received a single oral dose of cilofexor 30 mg (3 x 10 mg tablets ) or 10 mg (1 x 10 mg tablet) in a fed state, on Day 1. | 10 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Enrolled but Never Treated | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1: Mild Hepatic Impairment | Total | Cohort 3: Normal Hepatic Function | Cohort 3: Severe Hepatic Impairment | Cohort 1 & 2: Normal Hepatic Function | Cohort 2: Moderate Hepatic Impairment |
|---|---|---|---|---|---|---|
| Age, Continuous | 54 years STANDARD_DEVIATION 10.1 | 54.45 years STANDARD_DEVIATION 8.67 | 52 years STANDARD_DEVIATION 8.4 | 54 years STANDARD_DEVIATION 9.5 | 55 years STANDARD_DEVIATION 7.6 | 57 years STANDARD_DEVIATION 8.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 25 Participants | 5 Participants | 6 Participants | 7 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 31 Participants | 5 Participants | 4 Participants | 9 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 51 Participants | 9 Participants | 9 Participants | 15 Participants | 10 Participants |
| Region of Enrollment New Zealand | 2 participants | 8 participants | 1 participants | 1 participants | 3 participants | 1 participants |
| Region of Enrollment United States | 8 participants | 48 participants | 9 participants | 9 participants | 13 participants | 9 participants |
| Sex: Female, Male Female | 3 Participants | 16 Participants | 3 Participants | 3 Participants | 5 Participants | 2 Participants |
| Sex: Female, Male Male | 7 Participants | 40 Participants | 7 Participants | 7 Participants | 11 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 16 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 1 / 10 | 1 / 10 | 2 / 16 | 2 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 1 / 10 | 0 / 16 | 1 / 10 | 0 / 10 |
Outcome results
Primary
Pharmacokinetic (PK) Parameter: AUClast of Cilofexor
AUClast is defined as the concentration of drug from time zero to the last observable concentration.
Time frame: ≤ 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
Population: The PK Analysis Sets included all enrolled participants who took at least 1 dose of study drug and had at least 1 nonmissing postdose concentration value reported by the PK laboratory for the corresponding analytes. A participant with normal hepatic function might serve as a matched control across cohorts evaluating the same cilofexor dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Mild Hepatic Impairment | Pharmacokinetic (PK) Parameter: AUClast of Cilofexor | 5381.0 h*ng/mL | Standard Deviation 2175.34 |
| Cohort 1: Normal Hepatic Function | Pharmacokinetic (PK) Parameter: AUClast of Cilofexor | 2972.6 h*ng/mL | Standard Deviation 1230.49 |
| Cohort 2: Moderate Hepatic Impairment | Pharmacokinetic (PK) Parameter: AUClast of Cilofexor | 8223.7 h*ng/mL | Standard Deviation 7492.41 |
| Cohort 2: Normal Hepatic Function | Pharmacokinetic (PK) Parameter: AUClast of Cilofexor | 2756.7 h*ng/mL | Standard Deviation 851.38 |
| Cohort 3: Severe Hepatic Impairment | Pharmacokinetic (PK) Parameter: AUClast of Cilofexor | 6534.3 h*ng/mL | Standard Deviation 3791.05 |
| Cohort 3: Normal Hepatic Function | Pharmacokinetic (PK) Parameter: AUClast of Cilofexor | 960.0 h*ng/mL | Standard Deviation 352.71 |
Comparison: An analysis of variance (ANOVA) model with hepatic function group as a fixed effect was fitted to the natural logarithmic transformation of PK parameters (AUClast) for each cohort.90% CI: [1.2885, 2.4781]
Comparison: An ANOVA model with hepatic function group as a fixed effect was fitted to the natural logarithmic transformation of PK parameters (AUClast) for each cohort.90% CI: [1.6735, 3.6954]
Comparison: An ANOVA model with hepatic function group as a fixed effect was fitted to the natural logarithmic transformation of PK parameters (AUClast) for each cohort.90% CI: [4.3675, 9.1569]
Primary
PK Parameter: %AUCexp of Cilofexor
%AUCexp is defined as the percentage of AUC extrapolated between AUClast and AUCinf.
Time frame: ≤ 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
Population: Participants in the PK Analysis Set were analyzed. A participant with normal hepatic function might serve as a matched control across cohorts evaluating the same cilofexor dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Mild Hepatic Impairment | PK Parameter: %AUCexp of Cilofexor | 0.63 percentage of AUCexp | Standard Deviation 0.27 |
| Cohort 1: Normal Hepatic Function | PK Parameter: %AUCexp of Cilofexor | 1.95 percentage of AUCexp | Standard Deviation 1.621 |
| Cohort 2: Moderate Hepatic Impairment | PK Parameter: %AUCexp of Cilofexor | 0.64 percentage of AUCexp | Standard Deviation 0.194 |
| Cohort 2: Normal Hepatic Function | PK Parameter: %AUCexp of Cilofexor | 1.87 percentage of AUCexp | Standard Deviation 1.653 |
| Cohort 3: Severe Hepatic Impairment | PK Parameter: %AUCexp of Cilofexor | 1.81 percentage of AUCexp | Standard Deviation 1.874 |
| Cohort 3: Normal Hepatic Function | PK Parameter: %AUCexp of Cilofexor | 2.96 percentage of AUCexp | Standard Deviation 1.962 |
Primary
PK Parameter: AUCinf of Cilofexor
AUCinf is defined as the concentration of drug extrapolated to infinite time.
Time frame: ≤ 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
Population: Participants in the PK Analysis Set were analyzed. A participant with normal hepatic function might serve as a matched control across cohorts evaluating the same cilofexor dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Mild Hepatic Impairment | PK Parameter: AUCinf of Cilofexor | 5411.9 h*ng/mL | Standard Deviation 2181.82 |
| Cohort 1: Normal Hepatic Function | PK Parameter: AUCinf of Cilofexor | 3024.3 h*ng/mL | Standard Deviation 1224.02 |
| Cohort 2: Moderate Hepatic Impairment | PK Parameter: AUCinf of Cilofexor | 8288.2 h*ng/mL | Standard Deviation 7583.42 |
| Cohort 2: Normal Hepatic Function | PK Parameter: AUCinf of Cilofexor | 2805.6 h*ng/mL | Standard Deviation 851.26 |
| Cohort 3: Severe Hepatic Impairment | PK Parameter: AUCinf of Cilofexor | 6719.4 h*ng/mL | Standard Deviation 4056.73 |
| Cohort 3: Normal Hepatic Function | PK Parameter: AUCinf of Cilofexor | 986.2 h*ng/mL | Standard Deviation 354.93 |
Comparison: An ANOVA model with hepatic function group as a fixed effect was fitted to the natural logarithmic transformation of PK parameters (AUCinf) for each cohort.90% CI: [1.275, 2.4374]
Comparison: An ANOVA model with hepatic function group as a fixed effect was fitted to the natural logarithmic transformation of PK parameters (AUCinf) for each cohort.90% CI: [1.6531, 3.6486]
Comparison: An ANOVA model with hepatic function group as a fixed effect was fitted to the natural logarithmic transformation of PK parameters (AUCinf) for each cohort.90% CI: [4.2965, 9.091]
Primary
PK Parameter: Clast of Cilofexor
Clast is defined as the last observable concentration of drug.
Time frame: ≤ 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
Population: Participants in the PK Analysis Set were analyzed. A participant with normal hepatic function might serve as a matched control across cohorts evaluating the same cilofexor dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Mild Hepatic Impairment | PK Parameter: Clast of Cilofexor | 1.97 ng/mL | Standard Deviation 1.005 |
| Cohort 1: Normal Hepatic Function | PK Parameter: Clast of Cilofexor | 3.84 ng/mL | Standard Deviation 2.162 |
| Cohort 2: Moderate Hepatic Impairment | PK Parameter: Clast of Cilofexor | 2.76 ng/mL | Standard Deviation 3.377 |
| Cohort 2: Normal Hepatic Function | PK Parameter: Clast of Cilofexor | 3.73 ng/mL | Standard Deviation 2.378 |
| Cohort 3: Severe Hepatic Impairment | PK Parameter: Clast of Cilofexor | 6.03 ng/mL | Standard Deviation 8.044 |
| Cohort 3: Normal Hepatic Function | PK Parameter: Clast of Cilofexor | 2.18 ng/mL | Standard Deviation 1.387 |
Primary
PK Parameter: CL/F of Cilofexor
CL/F is defined as the apparent oral clearance following administration of the drug.
Time frame: ≤ 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
Population: Participants in the PK Analysis Set were analyzed. A participant with normal hepatic function might serve as a matched control across cohorts evaluating the same cilofexor dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Mild Hepatic Impairment | PK Parameter: CL/F of Cilofexor | 6621.5 mL/h | Standard Deviation 3219.5 |
| Cohort 1: Normal Hepatic Function | PK Parameter: CL/F of Cilofexor | 11324.4 mL/h | Standard Deviation 4184.32 |
| Cohort 2: Moderate Hepatic Impairment | PK Parameter: CL/F of Cilofexor | 5264.4 mL/h | Standard Deviation 2686.26 |
| Cohort 2: Normal Hepatic Function | PK Parameter: CL/F of Cilofexor | 11631.7 mL/h | Standard Deviation 3666.25 |
| Cohort 3: Severe Hepatic Impairment | PK Parameter: CL/F of Cilofexor | 1963.1 mL/h | Standard Deviation 964.19 |
| Cohort 3: Normal Hepatic Function | PK Parameter: CL/F of Cilofexor | 11535.9 mL/h | Standard Deviation 4627.39 |
Primary
PK Parameter: Cmax of Cilofexor
Cmax is defined as the maximum concentration of drug.
Time frame: ≤ 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
Population: Participants in the PK Analysis Set were analyzed. A participant with normal hepatic function might serve as a matched control across cohorts evaluating the same cilofexor dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Mild Hepatic Impairment | PK Parameter: Cmax of Cilofexor | 994.1 ng/mL | Standard Deviation 533.38 |
| Cohort 1: Normal Hepatic Function | PK Parameter: Cmax of Cilofexor | 603.5 ng/mL | Standard Deviation 275.33 |
| Cohort 2: Moderate Hepatic Impairment | PK Parameter: Cmax of Cilofexor | 909.2 ng/mL | Standard Deviation 477.2 |
| Cohort 2: Normal Hepatic Function | PK Parameter: Cmax of Cilofexor | 495.7 ng/mL | Standard Deviation 199.45 |
| Cohort 3: Severe Hepatic Impairment | PK Parameter: Cmax of Cilofexor | 426.6 ng/mL | Standard Deviation 136.4 |
| Cohort 3: Normal Hepatic Function | PK Parameter: Cmax of Cilofexor | 182.4 ng/mL | Standard Deviation 86.67 |
Comparison: An ANOVA model with hepatic function group as a fixed effect was fitted to the natural logarithmic transformation of PK parameters (Cmax) for each cohort.90% CI: [1.0723, 2.2995]
Comparison: An ANOVA model with hepatic function group as a fixed effect was fitted to the natural logarithmic transformation of PK parameters (Cmax) for each cohort.90% CI: [1.2193, 2.4667]
Comparison: An ANOVA model with hepatic function group as a fixed effect was fitted to the natural logarithmic transformation of PK parameters (Cmax) for each cohort.90% CI: [1.7562, 3.6648]
Primary
PK Parameter: t1/2 of Cilofexor
t1/2 is defined as the estimate of the terminal elimination half-life of the drug.
Time frame: ≤ 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
Population: Participants in the PK Analysis Set were analyzed. A participant with normal hepatic function might serve as a matched control across cohorts evaluating the same cilofexor dose.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Mild Hepatic Impairment | PK Parameter: t1/2 of Cilofexor | 11.45 hours |
| Cohort 1: Normal Hepatic Function | PK Parameter: t1/2 of Cilofexor | 9.49 hours |
| Cohort 2: Moderate Hepatic Impairment | PK Parameter: t1/2 of Cilofexor | 13.53 hours |
| Cohort 2: Normal Hepatic Function | PK Parameter: t1/2 of Cilofexor | 8.12 hours |
| Cohort 3: Severe Hepatic Impairment | PK Parameter: t1/2 of Cilofexor | 15.90 hours |
| Cohort 3: Normal Hepatic Function | PK Parameter: t1/2 of Cilofexor | 9.31 hours |
Primary
PK Parameter: Tlast of Cilofexor
Tlast is defined as the time (observed time point) of Clast.
Time frame: ≤ 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
Population: Participants in the PK Analysis Set were analyzed. A participant with normal hepatic function might serve as a matched control across cohorts evaluating the same cilofexor dose.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Mild Hepatic Impairment | PK Parameter: Tlast of Cilofexor | 64.80 hours |
| Cohort 1: Normal Hepatic Function | PK Parameter: Tlast of Cilofexor | 48.00 hours |
| Cohort 2: Moderate Hepatic Impairment | PK Parameter: Tlast of Cilofexor | 72.00 hours |
| Cohort 2: Normal Hepatic Function | PK Parameter: Tlast of Cilofexor | 48.00 hours |
| Cohort 3: Severe Hepatic Impairment | PK Parameter: Tlast of Cilofexor | 96.00 hours |
| Cohort 3: Normal Hepatic Function | PK Parameter: Tlast of Cilofexor | 48.00 hours |
Primary
PK Parameter: Tmax of Cilofexor
Tmax is defined as the time (observed time point) of Cmax.
Time frame: ≤ 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
Population: Participants in the PK Analysis Set were analyzed. A participant with normal hepatic function might serve as a matched control across cohorts evaluating the same cilofexor dose.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Mild Hepatic Impairment | PK Parameter: Tmax of Cilofexor | 3.75 hours |
| Cohort 1: Normal Hepatic Function | PK Parameter: Tmax of Cilofexor | 3.00 hours |
| Cohort 2: Moderate Hepatic Impairment | PK Parameter: Tmax of Cilofexor | 4.50 hours |
| Cohort 2: Normal Hepatic Function | PK Parameter: Tmax of Cilofexor | 3.75 hours |
| Cohort 3: Severe Hepatic Impairment | PK Parameter: Tmax of Cilofexor | 5.00 hours |
| Cohort 3: Normal Hepatic Function | PK Parameter: Tmax of Cilofexor | 4.00 hours |
Primary
PK Parameter: Vz/F of Cilofexor
Vz/F is defined as the apparent volume of distribution of the drug.
Time frame: ≤ 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
Population: Participants in the PK Analysis Set were analyzed. A participant with normal hepatic function might serve as a matched control across cohorts evaluating the same cilofexor dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Mild Hepatic Impairment | PK Parameter: Vz/F of Cilofexor | 97797.6 mL | Standard Deviation 18500.74 |
| Cohort 1: Normal Hepatic Function | PK Parameter: Vz/F of Cilofexor | 148898.5 mL | Standard Deviation 81520.19 |
| Cohort 2: Moderate Hepatic Impairment | PK Parameter: Vz/F of Cilofexor | 99541.7 mL | Standard Deviation 31192.41 |
| Cohort 2: Normal Hepatic Function | PK Parameter: Vz/F of Cilofexor | 153854.9 mL | Standard Deviation 83844.37 |
| Cohort 3: Severe Hepatic Impairment | PK Parameter: Vz/F of Cilofexor | 41375.1 mL | Standard Deviation 11767.71 |
| Cohort 3: Normal Hepatic Function | PK Parameter: Vz/F of Cilofexor | 160423.9 mL | Standard Deviation 92259.03 |
Primary
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.
Time frame: ≤ 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
Population: Participants in the PK Analysis Set were analyzed. A participant with normal hepatic function might serve as a matched control across cohorts evaluating the same cilofexor dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Mild Hepatic Impairment | PK Parameter: λz of Cilofexor | 0.070 1/hour | Standard Deviation 0.0377 |
| Cohort 1: Normal Hepatic Function | PK Parameter: λz of Cilofexor | 0.099 1/hour | Standard Deviation 0.0661 |
| Cohort 2: Moderate Hepatic Impairment | PK Parameter: λz of Cilofexor | 0.051 1/hour | Standard Deviation 0.0152 |
| Cohort 2: Normal Hepatic Function | PK Parameter: λz of Cilofexor | 0.100 1/hour | Standard Deviation 0.0655 |
| Cohort 3: Severe Hepatic Impairment | PK Parameter: λz of Cilofexor | 0.045 1/hour | Standard Deviation 0.0117 |
| Cohort 3: Normal Hepatic Function | PK Parameter: λz of Cilofexor | 0.099 1/hour | Standard Deviation 0.0659 |
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.
Time frame: 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
Population: Participants in the PD Analysis Set were analyzed. A participant with normal hepatic function might serve as a matched control across cohorts evaluating the same cilofexor dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Mild Hepatic Impairment | PD Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for Fibroblast Growth Factor 19 (FGF19) | 3.031 ratio | Standard Deviation 1.0376 |
| Cohort 1: Normal Hepatic Function | PD Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for Fibroblast Growth Factor 19 (FGF19) | 2.840 ratio | Standard Deviation 0.9254 |
| Cohort 2: Moderate Hepatic Impairment | PD Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for Fibroblast Growth Factor 19 (FGF19) | 3.730 ratio | Standard Deviation 1.3768 |
| Cohort 2: Normal Hepatic Function | PD Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for Fibroblast Growth Factor 19 (FGF19) | 2.848 ratio | Standard Deviation 1.025 |
| Cohort 3: Severe Hepatic Impairment | PD Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for Fibroblast Growth Factor 19 (FGF19) | 1.582 ratio | Standard Deviation 0.8182 |
| Cohort 3: Normal Hepatic Function | PD Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for Fibroblast Growth Factor 19 (FGF19) | 2.179 ratio | Standard Deviation 1.6972 |
90% CI: [0.8275, 1.3726]
90% CI: [0.9663, 1.7334]
90% CI: [0.5479, 1.2347]
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.
Time frame: 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
Population: Participants in the PD Analysis Set were analyzed. A participant with normal hepatic function might serve as a matched control across cohorts evaluating the same cilofexor dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Mild Hepatic Impairment | PD Parameter: Mean Day 1/ Day -1 Ratio of Cmax for Fibroblast Growth Factor 19 (FGF19) | 3.778 ratio | Standard Deviation 1.4954 |
| Cohort 1: Normal Hepatic Function | PD Parameter: Mean Day 1/ Day -1 Ratio of Cmax for Fibroblast Growth Factor 19 (FGF19) | 3.494 ratio | Standard Deviation 1.4423 |
| Cohort 2: Moderate Hepatic Impairment | PD Parameter: Mean Day 1/ Day -1 Ratio of Cmax for Fibroblast Growth Factor 19 (FGF19) | 4.459 ratio | Standard Deviation 1.9899 |
| Cohort 2: Normal Hepatic Function | PD Parameter: Mean Day 1/ Day -1 Ratio of Cmax for Fibroblast Growth Factor 19 (FGF19) | 3.145 ratio | Standard Deviation 1.4484 |
| Cohort 3: Severe Hepatic Impairment | PD Parameter: Mean Day 1/ Day -1 Ratio of Cmax for Fibroblast Growth Factor 19 (FGF19) | 1.899 ratio | Standard Deviation 1.1619 |
| Cohort 3: Normal Hepatic Function | PD Parameter: Mean Day 1/ Day -1 Ratio of Cmax for Fibroblast Growth Factor 19 (FGF19) | 2.098 ratio | Standard Deviation 1.1579 |
90% CI: [0.791, 1.4762]
90% CI: [0.9663, 1.9506]
90% CI: [0.6142, 1.3275]
Secondary
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.
Time frame: 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
Population: Participants in the PD Analysis Set were analyzed. A participant with normal hepatic function might serve as a matched control across cohorts evaluating the same cilofexor dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Mild Hepatic Impairment | PD Parameter: Mean Day 1/ Day -1 Ratio of Cmin for α-hydroxy-4-cholesten-3-one (C4) | 0.599 ratio | Standard Deviation 0.3272 |
| Cohort 1: Normal Hepatic Function | PD Parameter: Mean Day 1/ Day -1 Ratio of Cmin for α-hydroxy-4-cholesten-3-one (C4) | 0.707 ratio | Standard Deviation 0.2838 |
| Cohort 2: Moderate Hepatic Impairment | PD Parameter: Mean Day 1/ Day -1 Ratio of Cmin for α-hydroxy-4-cholesten-3-one (C4) | 0.668 ratio | Standard Deviation 0.2384 |
| Cohort 2: Normal Hepatic Function | PD Parameter: Mean Day 1/ Day -1 Ratio of Cmin for α-hydroxy-4-cholesten-3-one (C4) | 0.583 ratio | Standard Deviation 0.1634 |
| Cohort 3: Severe Hepatic Impairment | PD Parameter: Mean Day 1/ Day -1 Ratio of Cmin for α-hydroxy-4-cholesten-3-one (C4) | 0.953 ratio | Standard Deviation 0.2073 |
| Cohort 3: Normal Hepatic Function | PD Parameter: Mean Day 1/ Day -1 Ratio of Cmin for α-hydroxy-4-cholesten-3-one (C4) | 0.727 ratio | Standard Deviation 0.2674 |
90% CI: [0.5837, 1.1486]
90% CI: [0.8772, 1.4615]
90% CI: [1.0468, 1.7574]
Secondary
Percentage of Participants Experiencing Treatment-Emergent Adverse Events
Time frame: Day 1 up to Day 31
Population: The Safety Analysis Set included all participants who took at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Mild Hepatic Impairment | Percentage of Participants Experiencing Treatment-Emergent Adverse Events | 10.0 percentage of participants |
| Cohort 1: Normal Hepatic Function | Percentage of Participants Experiencing Treatment-Emergent Adverse Events | 20.0 percentage of participants |
| Cohort 2: Moderate Hepatic Impairment | Percentage of Participants Experiencing Treatment-Emergent Adverse Events | 12.5 percentage of participants |
| Cohort 2: Normal Hepatic Function | Percentage of Participants Experiencing Treatment-Emergent Adverse Events | 30.0 percentage of participants |
| Cohort 3: Severe Hepatic Impairment | Percentage of Participants Experiencing Treatment-Emergent Adverse Events | 0 percentage of participants |
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.
Time frame: Day 1 up to Day 31
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Mild Hepatic Impairment | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Any Laboratory Abnormality | 90.0 percentage of participants |
| Cohort 1: Mild Hepatic Impairment | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Grade 3 or above Laboratory Abnormalities | 20.0 percentage of participants |
| Cohort 1: Normal Hepatic Function | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Any Laboratory Abnormality | 100.0 percentage of participants |
| Cohort 1: Normal Hepatic Function | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Grade 3 or above Laboratory Abnormalities | 20.0 percentage of participants |
| Cohort 2: Moderate Hepatic Impairment | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Any Laboratory Abnormality | 50.0 percentage of participants |
| Cohort 2: Moderate Hepatic Impairment | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Grade 3 or above Laboratory Abnormalities | 0 percentage of participants |
| Cohort 2: Normal Hepatic Function | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Grade 3 or above Laboratory Abnormalities | 40.0 percentage of participants |
| Cohort 2: Normal Hepatic Function | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Any Laboratory Abnormality | 100.0 percentage of participants |
| Cohort 3: Severe Hepatic Impairment | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Any Laboratory Abnormality | 60.0 percentage of participants |
| Cohort 3: Severe Hepatic Impairment | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Grade 3 or above Laboratory Abnormalities | 0 percentage of participants |
Secondary
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.
Time frame: 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
Population: Participants in the PD Analysis Set were analyzed. A participant with normal hepatic function might serve as a matched control across cohorts evaluating the same cilofexor dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Mild Hepatic Impairment | Pharmacodynamic (PD) Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for α-hydroxy-4-cholesten-3-one (C4) | 0.706 ratio | Standard Deviation 0.2273 |
| Cohort 1: Normal Hepatic Function | Pharmacodynamic (PD) Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for α-hydroxy-4-cholesten-3-one (C4) | 0.817 ratio | Standard Deviation 0.2836 |
| Cohort 2: Moderate Hepatic Impairment | Pharmacodynamic (PD) Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for α-hydroxy-4-cholesten-3-one (C4) | 0.716 ratio | Standard Deviation 0.237 |
| Cohort 2: Normal Hepatic Function | Pharmacodynamic (PD) Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for α-hydroxy-4-cholesten-3-one (C4) | 0.681 ratio | Standard Deviation 0.2614 |
| Cohort 3: Severe Hepatic Impairment | Pharmacodynamic (PD) Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for α-hydroxy-4-cholesten-3-one (C4) | 1.063 ratio | Standard Deviation 0.2469 |
| Cohort 3: Normal Hepatic Function | Pharmacodynamic (PD) Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for α-hydroxy-4-cholesten-3-one (C4) | 0.978 ratio | Standard Deviation 0.4155 |
90% CI: [0.6827, 1.1144]
90% CI: [0.8295, 1.3883]
90% CI: [0.8783, 1.4992]