Pharmacokinetics and Pharmacodynamics of Cilofexor in Adults With Normal and Impaired Hepatic Function
- Conditions
- Nonalcoholic Steatohepatitis (NASH)Primary Sclerosing Cholangitis (PSC)
- Interventions
- Registration Number
- NCT02808312
- Lead Sponsor
- Gilead Sciences
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 57
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.
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort 2: Moderate Hepatic Impairment Cilofexor Participants with moderate hepatic impairment will receive a single oral dose of cilofexor 30 mg (3 x 10 mg tablets). Cohort 1: Mild Hepatic Impairment Cilofexor Participants with mild hepatic impairment will receive a single oral dose of cilofexor 30 mg (3 x 10 mg tablets). Cohort 1: Normal Hepatic Function Cilofexor 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). Cohort 2: Normal Hepatic Function Cilofexor 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). Cohort 3: Severe Hepatic Impairment Cilofexor Participants with severe hepatic impairment will receive a single oral dose of cilofexor 10 mg (1 x 10 mg tablet). Cohort 3: Normal Hepatic Function Cilofexor 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).
- Primary Outcome Measures
Name Time Method 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.
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.
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: %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: 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: 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: 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.
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: 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.
- Secondary Outcome Measures
Name Time Method Percentage of Participants Experiencing Treatment-Emergent Adverse Events 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) 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.
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.
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.