Digestive System Diseases, Hepatic Impairment, Liver Diseases
Conditions
Keywords
Hepatic Impairment, Pharmacokinetics, Pharmacodynamics
Brief summary
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.
Interventions
DRUGIDN-6556
Sponsors
Conatus Pharmaceuticals Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
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: 1. Mean body weight within ±15 kg 2. Mean age within ±10 years 3. Similar gender ratio Subjects with Hepatic Impairment: * Evidence of hepatic disease 1. Score ≥ 2 on one of the Child-Pugh parameters, or 2. Histological or imaging diagnosis of cirrhosis, or 3. Presence of esophageal varices, or 4. 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 1. Mild hepatic impairment: Class A (Child-Pugh Scores 5-6 points) 2. Moderate hepatic impairment: Class B (Child-Pugh Scores 7-9 points) 3. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC | 48 Hours | Area under the plasma concentration curve (AUC) to 12 hours post-dose (AUC0-12); AUC to the last observed plasma concentration (AUClast); |
| Cmax | 48 Hours | Maximum concentration (Cmax) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Levels of cCK18/M30 | predose, 0.5, 1,2,3,4,5,8,12,24, and 48 hours post dose | Caspase-cleaved cytokeratin levels (cCK18M30) |
| Levels of Caspase 3/7 RLU | predose, 0.5, 1,2,3,4,5,8,12,24, and 48 hours post dose | Concentration of Caspase 3/7 Relative Light Units |
Countries
United States
Participant flow
Recruitment details
This was an open-label, multicenter, parallel-group study to compare the PK and PD 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 (subjects with normal hepatic function).
Pre-assignment details
A total of 37 subjects were dosed. One subject was dosed twice at two different centers, so the analyzed sample size was 36 subjects: 12 subjects with mild, and 8 subjects each with moderate and severe hepatic impairment, and with normal hepatic function.
Participants by arm
| Arm | Count |
|---|---|
| Child-Pugh Class A Mild Hepatic Impairment | 12 |
| Child-Pugh Class B Moderate Hepatic Impairment | 8 |
| Child-Pugh Class C Severe Hepatic Impairment | 8 |
| Normal Hepatic Function Medically healthy as determined by the investigator | 8 |
| Total | 36 |
Baseline characteristics
| Characteristic | Child-Pugh Class A | Total | Normal Hepatic Function | Child-Pugh Class C | Child-Pugh Class B |
|---|---|---|---|---|---|
| Age, Continuous | 54.8 years STANDARD_DEVIATION 8.8 | 55.9 years STANDARD_DEVIATION 6.8 | 57.6 years STANDARD_DEVIATION 4.9 | 57.4 years STANDARD_DEVIATION 4.8 | 54.1 years STANDARD_DEVIATION 7.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 17 Participants | 5 Participants | 4 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 19 Participants | 3 Participants | 4 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 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 |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 33 Participants | 7 Participants | 8 Participants | 8 Participants |
| Region of Enrollment United States | 12 participants | 36 participants | 8 participants | 8 participants | 8 participants |
| Sex: Female, Male Female | 4 Participants | 9 Participants | 2 Participants | 3 Participants | 0 Participants |
| Sex: Female, Male Male | 8 Participants | 27 Participants | 6 Participants | 5 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 12 / 36 |
| serious Total, serious adverse events | 0 / 36 |
Outcome results
Primary
AUC
Area under the plasma concentration curve (AUC) to 12 hours post-dose (AUC0-12); AUC to the last observed plasma concentration (AUClast);
Time frame: 48 Hours
Population: The analyzed sample size was 36 subjects: 12 subjects with mild, and 8 subjects each with moderate and severe hepatic impairment, and with normal hepatic function.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function | AUC | AUC0-12 (h*ng/mL) | 113.5 h*ng/mL | Geometric Coefficient of Variation 51.1 |
| Normal Hepatic Function | AUC | AUClast (h*ng/mL) | 120.6 h*ng/mL | Geometric Coefficient of Variation 47.1 |
| Child-Pugh Class A | AUC | AUClast (h*ng/mL) | 118.2 h*ng/mL | Geometric Coefficient of Variation 33 |
| Child-Pugh Class A | AUC | AUC0-12 (h*ng/mL) | 114.6 h*ng/mL | Geometric Coefficient of Variation 36 |
| Child-Pugh Class B | AUC | AUC0-12 (h*ng/mL) | 423.7 h*ng/mL | Geometric Coefficient of Variation 126.1 |
| Child-Pugh Class B | AUC | AUClast (h*ng/mL) | 435.7 h*ng/mL | Geometric Coefficient of Variation 121.7 |
| Child-Pugh Class C | AUC | AUC0-12 (h*ng/mL) | 1042 h*ng/mL | Geometric Coefficient of Variation 27.8 |
| Child-Pugh Class C | AUC | AUClast (h*ng/mL) | 1083 h*ng/mL | Geometric Coefficient of Variation 26.9 |
Primary
Cmax
Maximum concentration (Cmax)
Time frame: 48 Hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Cmax | 26.01 ng/mL | Geometric Coefficient of Variation 70.4 |
| Child-Pugh Class A | Cmax | 37.45 ng/mL | Geometric Coefficient of Variation 64.9 |
| Child-Pugh Class B | Cmax | 127.2 ng/mL | Geometric Coefficient of Variation 146.6 |
| Child-Pugh Class C | Cmax | 322.2 ng/mL | Geometric Coefficient of Variation 40.9 |
Secondary
Levels of Caspase 3/7 RLU
Concentration of Caspase 3/7 Relative Light Units
Time frame: predose, 0.5, 1,2,3,4,5,8,12,24, and 48 hours post dose
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Normal Hepatic Function | Levels of Caspase 3/7 RLU | 24 hours post dose | 842.0 RLU |
| Normal Hepatic Function | Levels of Caspase 3/7 RLU | 5 hours post dose | 836.5 RLU |
| Normal Hepatic Function | Levels of Caspase 3/7 RLU | 12 hours post dose | 876.5 RLU |
| Normal Hepatic Function | Levels of Caspase 3/7 RLU | 2 hours post dose | 820.0 RLU |
| Normal Hepatic Function | Levels of Caspase 3/7 RLU | .5 hour post dose | 900.5 RLU |
| Normal Hepatic Function | Levels of Caspase 3/7 RLU | 3 hours post dose | 872.0 RLU |
| Normal Hepatic Function | Levels of Caspase 3/7 RLU | Predose | 963.5 RLU |
| Normal Hepatic Function | Levels of Caspase 3/7 RLU | 48 hours post dose | 991.5 RLU |
| Normal Hepatic Function | Levels of Caspase 3/7 RLU | 8 hours post dose | 916.0 RLU |
| Normal Hepatic Function | Levels of Caspase 3/7 RLU | 4 hours post dose | 848.5 RLU |
| Normal Hepatic Function | Levels of Caspase 3/7 RLU | 1 hour post dose | 850.5 RLU |
| Child-Pugh Class A | Levels of Caspase 3/7 RLU | 12 hours post dose | 1039.0 RLU |
| Child-Pugh Class A | Levels of Caspase 3/7 RLU | 24 hours post dose | 1227.5 RLU |
| Child-Pugh Class A | Levels of Caspase 3/7 RLU | 48 hours post dose | 1291.0 RLU |
| Child-Pugh Class A | Levels of Caspase 3/7 RLU | 1 hour post dose | 1260.5 RLU |
| Child-Pugh Class A | Levels of Caspase 3/7 RLU | Predose | 1158.5 RLU |
| Child-Pugh Class A | Levels of Caspase 3/7 RLU | 2 hours post dose | 1048.0 RLU |
| Child-Pugh Class A | Levels of Caspase 3/7 RLU | 3 hours post dose | 1027.0 RLU |
| Child-Pugh Class A | Levels of Caspase 3/7 RLU | 4 hours post dose | 921.0 RLU |
| Child-Pugh Class A | Levels of Caspase 3/7 RLU | 5 hours post dose | 976.0 RLU |
| Child-Pugh Class A | Levels of Caspase 3/7 RLU | 8 hours post dose | 1088.5 RLU |
| Child-Pugh Class A | Levels of Caspase 3/7 RLU | .5 hour post dose | 1130.5 RLU |
| Child-Pugh Class B | Levels of Caspase 3/7 RLU | 48 hours post dose | 1754.0 RLU |
| Child-Pugh Class B | Levels of Caspase 3/7 RLU | 12 hours post dose | 1230.5 RLU |
| Child-Pugh Class B | Levels of Caspase 3/7 RLU | 4 hours post dose | 984.5 RLU |
| Child-Pugh Class B | Levels of Caspase 3/7 RLU | 8 hours post dose | 1084.5 RLU |
| Child-Pugh Class B | Levels of Caspase 3/7 RLU | 5 hours post dose | 903.5 RLU |
| Child-Pugh Class B | Levels of Caspase 3/7 RLU | 24 hours post dose | 1798.5 RLU |
| Child-Pugh Class B | Levels of Caspase 3/7 RLU | Predose | 2006.0 RLU |
| Child-Pugh Class B | Levels of Caspase 3/7 RLU | 2 hours post dose | 1121.0 RLU |
| Child-Pugh Class B | Levels of Caspase 3/7 RLU | .5 hour post dose | 2027.0 RLU |
| Child-Pugh Class B | Levels of Caspase 3/7 RLU | 3 hours post dose | 906.5 RLU |
| Child-Pugh Class B | Levels of Caspase 3/7 RLU | 1 hour post dose | 1482.0 RLU |
| Child-Pugh Class C | Levels of Caspase 3/7 RLU | 5 hours post dose | 776.0 RLU |
| Child-Pugh Class C | Levels of Caspase 3/7 RLU | Predose | 1662.5 RLU |
| Child-Pugh Class C | Levels of Caspase 3/7 RLU | .5 hour post dose | 1933.5 RLU |
| Child-Pugh Class C | Levels of Caspase 3/7 RLU | 1 hour post dose | 1392.0 RLU |
| Child-Pugh Class C | Levels of Caspase 3/7 RLU | 2 hours post dose | 1090.0 RLU |
| Child-Pugh Class C | Levels of Caspase 3/7 RLU | 3 hours post dose | 796.0 RLU |
| Child-Pugh Class C | Levels of Caspase 3/7 RLU | 4 hours post dose | 806.5 RLU |
| Child-Pugh Class C | Levels of Caspase 3/7 RLU | 8 hours post dose | 893.5 RLU |
| Child-Pugh Class C | Levels of Caspase 3/7 RLU | 12 hours post dose | 1187.0 RLU |
| Child-Pugh Class C | Levels of Caspase 3/7 RLU | 24 hours post dose | 1276.0 RLU |
| Child-Pugh Class C | Levels of Caspase 3/7 RLU | 48 hours post dose | 1457.5 RLU |
Secondary
Levels of cCK18/M30
Caspase-cleaved cytokeratin levels (cCK18M30)
Time frame: predose, 0.5, 1,2,3,4,5,8,12,24, and 48 hours post dose
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Normal Hepatic Function | Levels of cCK18/M30 | 12 hours post dose | 175.5 U/L |
| Normal Hepatic Function | Levels of cCK18/M30 | 8 hours post dose | 146.0 U/L |
| Normal Hepatic Function | Levels of cCK18/M30 | 5 hours post dose | 157.5 U/L |
| Normal Hepatic Function | Levels of cCK18/M30 | 1 hour post dose | 155.5 U/L |
| Normal Hepatic Function | Levels of cCK18/M30 | 4 hours post dose | 161.5 U/L |
| Normal Hepatic Function | Levels of cCK18/M30 | 48 hours post dose | 213.0 U/L |
| Normal Hepatic Function | Levels of cCK18/M30 | 0.5 hour post dose | 147.0 U/L |
| Normal Hepatic Function | Levels of cCK18/M30 | 2 hours post dose | 149.0 U/L |
| Normal Hepatic Function | Levels of cCK18/M30 | 24 hours post dose | 163.5 U/L |
| Normal Hepatic Function | Levels of cCK18/M30 | 3 hours post dose | 181.5 U/L |
| Normal Hepatic Function | Levels of cCK18/M30 | Predose | 161.5 U/L |
| Child-Pugh Class A | Levels of cCK18/M30 | 4 hours post dose | 156.5 U/L |
| Child-Pugh Class A | Levels of cCK18/M30 | 12 hours post dose | 104.5 U/L |
| Child-Pugh Class A | Levels of cCK18/M30 | 5 hours post dose | 161.5 U/L |
| Child-Pugh Class A | Levels of cCK18/M30 | Predose | 147.5 U/L |
| Child-Pugh Class A | Levels of cCK18/M30 | 8 hours post dose | 126.0 U/L |
| Child-Pugh Class A | Levels of cCK18/M30 | 0.5 hour post dose | 153.0 U/L |
| Child-Pugh Class A | Levels of cCK18/M30 | 2 hours post dose | 153.0 U/L |
| Child-Pugh Class A | Levels of cCK18/M30 | 3 hours post dose | 167.0 U/L |
| Child-Pugh Class A | Levels of cCK18/M30 | 1 hour post dose | 170.5 U/L |
| Child-Pugh Class A | Levels of cCK18/M30 | 48 hours post dose | 193.0 U/L |
| Child-Pugh Class A | Levels of cCK18/M30 | 24 hours post dose | 151.0 U/L |
| Child-Pugh Class B | Levels of cCK18/M30 | 24 hours post dose | 298.0 U/L |
| Child-Pugh Class B | Levels of cCK18/M30 | 3 hours post dose | 322.5 U/L |
| Child-Pugh Class B | Levels of cCK18/M30 | 2 hours post dose | 376.5 U/L |
| Child-Pugh Class B | Levels of cCK18/M30 | Predose | 348.0 U/L |
| Child-Pugh Class B | Levels of cCK18/M30 | 0.5 hour post dose | 433.5 U/L |
| Child-Pugh Class B | Levels of cCK18/M30 | 1 hour post dose | 380.5 U/L |
| Child-Pugh Class B | Levels of cCK18/M30 | 4 hours post dose | 295.5 U/L |
| Child-Pugh Class B | Levels of cCK18/M30 | 5 hours post dose | 229.0 U/L |
| Child-Pugh Class B | Levels of cCK18/M30 | 8 hours post dose | 190.5 U/L |
| Child-Pugh Class B | Levels of cCK18/M30 | 12 hours post dose | 137.5 U/L |
| Child-Pugh Class B | Levels of cCK18/M30 | 48 hours post dose | 353.5 U/L |
| Child-Pugh Class C | Levels of cCK18/M30 | 4 hours post dose | 362.0 U/L |
| Child-Pugh Class C | Levels of cCK18/M30 | 48 hours post dose | 508.5 U/L |
| Child-Pugh Class C | Levels of cCK18/M30 | 12 hours post dose | 287.5 U/L |
| Child-Pugh Class C | Levels of cCK18/M30 | 2 hours post dose | 446.5 U/L |
| Child-Pugh Class C | Levels of cCK18/M30 | 1 hour post dose | 471.0 U/L |
| Child-Pugh Class C | Levels of cCK18/M30 | 0.5 hour post dose | 506.5 U/L |
| Child-Pugh Class C | Levels of cCK18/M30 | 24 hours post dose | 423.0 U/L |
| Child-Pugh Class C | Levels of cCK18/M30 | Predose | 517.0 U/L |
| Child-Pugh Class C | Levels of cCK18/M30 | 3 hours post dose | 388.0 U/L |
| Child-Pugh Class C | Levels of cCK18/M30 | 8 hours post dose | 274.5 U/L |
| Child-Pugh Class C | Levels of cCK18/M30 | 5 hours post dose | 358.0 U/L |