Evaluation of the Pharmacokinetics of Tropifexor in Subjects With Mild, Moderate, or Severe Hepatic Impairment Compared to Healthy Control Subjects

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the effect of hepatic impairment on the systemic exposure of tropifexor and to evaluate the safety of tropifexor in subjects with hepatic impairment. The results of this study will support treatment and dosing decisions for patients with varying degrees of hepatic impairment.

Official Title
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A Phase 1, Open-label, Single-dose, Multi-center, Parallel Group Study to Evaluate the Pharmacokinetics of Tropifexor (LJN452) in Subjects With Mild, Moderate or Severe Hepatic Impairment Compared to Healthy Control Subjects

Conditions
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Non-alcoholic Fatty Liver Disease

Intervention / Treatment
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* Drug: LJN452


Participation Criteria
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Eligibility Criteria
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All subjects: Inclusions Criteria: Subjects must weight at least 50 kg, with a BMI within the range of 18 to 38 kg/m2 Must be willing to remain in the clinical research unit as required by the protocol Exclusion Criteria: Use of other study drugs at the time of enrollment, or within 5 half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations History of hypersensitivity to the study treatment or to drugs of similar chemical classes Pregnant or nursing women Women of child-bearing potential Healthy Volunteers: Inclusion Criteria: - In good health as determined by past medical history, physical examination, ECG, laboratory tests, and urinalysis at Screening. Exclusion Criteria: Liver disease or liver injury Chronic infection with Hepatitis B or Hepatitis C History or presence of impaired renal function Hepatically Impaired Subjects: Inclusion Criteria: - Hepatic impairment as defined by the Child-Pugh classification for severity of liver disease Exclusion Criteria: Severe complications of liver disease within the preceding 3 months Emergency room visit or hospitalization due to liver disease within the preceding 3 months for mildly and moderately hepatically impaired subjects, and within the preceding 1 month for severely hepatically impaired subjects Subject has received liver transplant at any time in the past and is on immunosuppressant therapy Acute Hepatitis B or Hepatitis C infection Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Group 1 - Normal Hepatic Function<br>Normal hepatic function - Control - control group | Drug: LJN452<br>* Dose A single dose<br>|
| Experimental: Group 2 - Mild Hepatic Impairment<br>Mild hepatic impairment - Child-Pugh A (Score 5-6) | Drug: LJN452<br>* Dose A single dose<br>|
| Experimental: Group 3 - Moderate Hepatic Impairment<br>Moderate hepatic impairment - Child-Pugh B (Score 7-9) | Drug: LJN452<br>* Dose A single dose<br>|
| Experimental: Group 4 - Severe Hepatic Impairment<br>Severe hepatic impairment - Child-Pugh C (score 10-15) | Drug: LJN452<br>* Dose A single dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | The maximum (peak) observed drug concentration after single dose administration (mass x volume-1) | Up to 8 days | 
| Tmax | Time to reach the maximum (peak) plasma drug concentration after single dose administration (time) | Up to 8 days | 
| AUClast | The area under the concentration-time curve from time zero to the time of the last quantifiable concentration sampling time (mass x time x volume-1) | Up to 8 days | 
| AUCinf | The area under the concentration-time curve from time zero to infinity (mass x time x volume-1) | Up to 8 days | 
| T1/2 | The elimination half-life associated with the terminal slope of a semi-logarithmic concentration-time curve | Up to 8 days | 
| CL/F | The apparent total body clearance of the drug from plasma (volume x time-1) | Up to 8 days | 
| Vz/F | The apparent volume of distribution during the terminal phase | Up to 8 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| fu | Fraction of analyte unbound calculated in-vitro | Day 1 | 
| Cmax,u | The maximum (peak) observed plasma drug concentration after single dose administration (Cmax) of unbound drug (mass x time x volume-1), calculated as Cmax*fu | Day 1 | 
| AUClast,u | The area under the concentration-time curve from time zero to the last quantifiable concentration sampling time of unbound drug (mass x time x volume-1), calculated as AUClast*fu | Day 1 | 
| AUCinf,u | The area under the concentration-time curve from time zero to infinity of unbound drug (mass x time x volume-1), calculated as AUCinf*fu | Day 1 | 
| CL/F,u | The apparent total body clearance of drug from the plasma of unbound drug (volume x time-1), calculated as CL/F/fu | Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LJN452, tropifexor, PK, safety, healthy subjects, hepatically impaired, Nonalcoholic Steatohepatitis, Nonalcoholic Fatty Liver Disease, NAFLD