PK and PD Study of IDN-6556 in Subjects With Hepatic Impairment and Matched Healthy Volunteers

Study Overview
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Brief Summary
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This is an open-label, parallel-group study to compare the pharmacokinetics and pharmacodynamics of IDN-6556 following a single 50 mg oral dose of IDN-6556 in subjects with mild, moderate, and severe hepatic impairment (defined as Child-Pugh A, B, and C, respectively) and matched healthy volunteers with normal hepatic function.

Official Title
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An Open-Label Pharmacokinetic and Pharmacodynamic Study of a Single Dose of IDN-6556 in Subjects With Hepatic Impairment and in Matched Healthy Volunteers

Conditions
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Hepatic Impairment, Liver Diseases, Digestive System Diseases

Intervention / Treatment
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* Drug: IDN-6556


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All Subjects: Male or female subjects 18 years of age or older, able to provide written informed consent, understand and comply with all scheduled visits, and other requirements of the study Body mass index (BMI) 18.0 - 40.0 kg/m2 and body weight >45 kg Willingness to utilize two reliable forms of contraception (for both males and females of childbearing potential) from Screening to one month after the last dose of study drug Matched Healthy Volunteers: Medically healthy as determined by the Investigator Supine blood pressure ≤145/90 mmHg No significant uncontrolled systemic or major illness that, in the opinion of the Investigator, would preclude the subject from participating in and completing the study Demographically comparable to subjects with hepatic impairment as follows: Mean body weight within ±15 kg Mean age within ±10 years Similar gender ratio Subjects with Hepatic Impairment: Evidence of hepatic disease Score ≥ 2 on one of the Child-Pugh parameters, or Histological or imaging diagnosis of cirrhosis, or Presence of esophageal varices, or Abnormal alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) levels Meet one of the following criteria for Child-Pugh classification for hepatic impairment during Screening Mild hepatic impairment: Class A (Child-Pugh Scores 5-6 points) Moderate hepatic impairment: Class B (Child-Pugh Scores 7-9 points) Severe hepatic impairment: Class C (Child Pugh Scores 10-15 points) Supine blood pressure ≤160/100 mmHg Exclusion Criteria: All Subjects: Known infection with human immunodeficiency virus (HIV) upon serological testing Evidence of clinically significant uncontrolled hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, renal, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing) Disorders or surgery of the gastrointestinal tract which may interfere with drug absorption or may otherwise influence the pharmacokinetics of the investigational medicinal product (e.g., inflammatory bowel disease, resections of the small or large intestine, etc.) History of febrile illness within 5 days prior to dosing Note: Subjects can be rescreened once afebrile and more than 5 days have elapsed since the febrile illness. Known ongoing drug abuse within one month prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during Screening and/or at Day -1 Subjects with active or history of malignancies other than curatively treated skin cancer (basal cell or squamous cell carcinomas) Dosing in another clinical trial within 30 days prior to the study drug administration If female: known pregnancy, positive urine or serum pregnancy test, or lactating/breastfeeding Matched Healthy Volunteers: Evidence of clinically significant liver disease or liver damage (e.g., hepatitis B or C, autoimmune hepatitis, primary biliary cirrhosis, non-alcoholic fatty liver disease, elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) that is considered clinically significant by the Investigator, etc.) Screening creatinine clearance <80 mL/min using the Cockcroft-Gault equation History or presence of clinically concerning cardiac arrhythmias, or prolongation of Screening (pre-treatment) QT or QTc interval of >450 milliseconds (msec) History of regular alcohol consumption exceeding 28 drinks/week (1 drink = 150 mL of wine or 360 mL of beer or 45 mL of spirits) within 6 months of Screening Subjects with Hepatic Impairment: Fluctuating or rapidly deteriorating hepatic function, as indicated by strongly varying or worsening of clinical and/or laboratory signs of hepatic impairment during Screening period and up to Day -1 (e.g., advanced ascites, infection of ascites, fever, active gastrointestinal bleeding) History of liver transplant, or have a transjugular intrahepatic portosystemic shunt, and/or have undergone portacaval shunting History or presence of clinically concerning cardiac arrhythmias, or prolongation of Screening (pre-treatment) QT or QTc interval of >480 milliseconds (msec) Screening creatinine clearance <50 mL/min using the Cockcroft-Gault equation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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 |
| --- | --- |
| Experimental: Chil-Pugh Class A<br>All subjects with mild hepatic impairment received a single 50 mg oral dose of IDN-6556 | Drug: IDN-6556<br> <br> * Other names: PF-03491390;|
| Experimental: Chil-Pugh Class B<br>All subjects with moderate hepatic impairment received a single 50 mg oral dose of IDN-6556 | Drug: IDN-6556<br> <br> * Other names: PF-03491390;|
| Experimental: Chil-Pugh Class C<br>All subjects with severe hepatic impairment received a single 50 mg oral dose of IDN-6556 | Drug: IDN-6556<br> <br> * Other names: PF-03491390;|
| Experimental: Normal Hepatic Function<br>All healthy volunteers subjects received a single 50 mg oral dose of IDN-6556 | Drug: IDN-6556<br> <br> * Other names: PF-03491390;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC | Area under the plasma concentration curve (AUC) to 12 hours post-dose (AUC0-12); AUC to the last observed plasma concentration (AUClast); | 48 Hours | 
| Cmax | Maximum concentration (Cmax) | 48 Hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Levels of cCK18/M30 | Caspase-cleaved cytokeratin levels (cCK18M30) | predose, 0.5, 1,2,3,4,5,8,12,24, and 48 hours post dose | 
| Levels of Caspase 3/7 RLU | Concentration of Caspase 3/7 Relative Light Units | predose, 0.5, 1,2,3,4,5,8,12,24, and 48 hours post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatic Impairment, Pharmacokinetics, Pharmacodynamics