Kidney Disease, Kidney Diseases, Renal Impairment, Renal Insufficiency
Conditions
Keywords
pharmacokinetics, pharmacodynamics, renal impairment
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 severe renal impairment and matched healthy volunteers with normal renal 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 - 75 years of age, 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 \>50 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 * Screening creatinine clearance ≥90 mL/min using the Cockcroft-Gault equation * 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 severe renal impairment as follows: 1. Mean body weight within ±10 kg 2. Mean age within ±5 years 3. Similar gender ratio Severe Renal Impaired Subjects: * Screening creatinine clearance (CLCR) \<30 mL/min using the Cockcroft-Gault equation * Supine blood pressure ≤170/110 mmHg * Documented renal impairment indicated by reduced creatinine clearance within 12 months of screening or longer * Stable renal function as evidenced by ≤30% difference in two measurements of creatinine clearance on two separate occasions separated by at least 28 days with one measurement being the value at screening.
Exclusion criteria
* History of renal trasplant * Acute renal failure * Subjects undergoing any method of dialysis or hemofiltration * Evidence or history of clinically significant uncontrolled hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, 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 * 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.) * Known infection with human immunodeficiency virus (HIV) upon serological testing * History or presence of clinically concerning cardiac arrhythmias, or prolongation of Screening (pre-treatment) QT or QTc interval of \>480 milliseconds (msec) for subjects with severe renal impairment or \>450 msec for matched healthy volunteers * Subjects with active or history of malignancies other than curatively treated skin cancer (basal cell or squamous cell carcinomas)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC | 48 hours | Area under the plasma concentration curve (AUC) parameters include AUC0-12, AUCinf, AUClast |
| Cmax | 48 hours | Maximum concentration (Cmax) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Levels of cCK18 | 48 hours | Biomarker cCK18 (Cleaved cytokeratin 18) PK evaluations from pre-dose to 48 hours |
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 severe renal impairment and matched subjects with normal renal function (healthy volunteers).
Pre-assignment details
In total, 16 subjects were enrolled and dosed (8 subjects with severe renal impairment, and 8 healthy volunteers) with one 50mg dose of IDN-6556.
Participants by arm
| Arm | Count |
|---|---|
| Healthy Volunteers Health Volunteers received one 50mg dose of IDN-6556 | 8 |
| Severe Renal Impairment Severe Renal Impairment subjects received one 50mg dose of IDN-6556 | 8 |
| Total | 16 |
Baseline characteristics
| Characteristic | Healthy Volunteers | Total | Severe Renal Impairment |
|---|---|---|---|
| Age, Continuous | 61.0 years | 62.0 years | 64.0 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 6 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 10 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 16 Participants | 8 Participants |
| Region of Enrollment United States | 8 participants | 16 participants | 8 participants |
| Sex: Female, Male Female | 4 Participants | 8 Participants | 4 Participants |
| Sex: Female, Male Male | 4 Participants | 8 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 16 |
| serious Total, serious adverse events | 0 / 16 |
Outcome results
Primary
AUC
Area under the plasma concentration curve (AUC) parameters include AUC0-12, AUCinf, AUClast
Time frame: 48 hours
Population: 7 subjects were used in the calculation of AUC0-inf for the healthy volunteer group as one subject had no identifiable terminal log-linear phase.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Volunteers | AUC | AUC 0-12 (h*ng/mL) | 102.0 h*ng/mL | Geometric Coefficient of Variation 39.4 |
| Healthy Volunteers | AUC | AUC 0-inf (h*ng/mL) | 107.4 h*ng/mL | Geometric Coefficient of Variation 41.3 |
| Healthy Volunteers | AUC | AUC last (h*ng/mL) | 105.9 h*ng/mL | Geometric Coefficient of Variation 38.3 |
| Severe Renal Impairment | AUC | AUC 0-12 (h*ng/mL) | 168.9 h*ng/mL | Geometric Coefficient of Variation 42.3 |
| Severe Renal Impairment | AUC | AUC 0-inf (h*ng/mL) | 188.5 h*ng/mL | Geometric Coefficient of Variation 43.8 |
| Severe Renal Impairment | AUC | AUC last (h*ng/mL) | 186.5 h*ng/mL | Geometric Coefficient of Variation 43.4 |
Primary
Cmax
Maximum concentration (Cmax)
Time frame: 48 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Healthy Volunteers | Cmax | 28.5 ng/mL | Geometric Coefficient of Variation 44 |
| Severe Renal Impairment | Cmax | 42.7 ng/mL | Geometric Coefficient of Variation 57 |
Secondary
Levels of cCK18
Biomarker cCK18 (Cleaved cytokeratin 18) PK evaluations from pre-dose to 48 hours
Time frame: 48 hours
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Healthy Volunteers | Levels of cCK18 | 8 hours | 178.0 U/L |
| Healthy Volunteers | Levels of cCK18 | predose | 240.0 U/L |
| Healthy Volunteers | Levels of cCK18 | .5 hour | 201.5 U/L |
| Healthy Volunteers | Levels of cCK18 | 1 hour | 208.0 U/L |
| Healthy Volunteers | Levels of cCK18 | 2 hours | 202.5 U/L |
| Healthy Volunteers | Levels of cCK18 | 3 hours | 184.5 U/L |
| Healthy Volunteers | Levels of cCK18 | 4 hours | 183.5 U/L |
| Healthy Volunteers | Levels of cCK18 | 5 hours | 179.0 U/L |
| Healthy Volunteers | Levels of cCK18 | 12 hours | 167.0 U/L |
| Healthy Volunteers | Levels of cCK18 | 24 hours | 204.0 U/L |
| Healthy Volunteers | Levels of cCK18 | 48 hours | 206.5 U/L |
| Severe Renal Impairment | Levels of cCK18 | 12 hours | 205.5 U/L |
| Severe Renal Impairment | Levels of cCK18 | 4 hours | 198.5 U/L |
| Severe Renal Impairment | Levels of cCK18 | predose | 223.5 U/L |
| Severe Renal Impairment | Levels of cCK18 | 48 hours | 195.0 U/L |
| Severe Renal Impairment | Levels of cCK18 | .5 hour | 202.5 U/L |
| Severe Renal Impairment | Levels of cCK18 | 5 hours | 221.5 U/L |
| Severe Renal Impairment | Levels of cCK18 | 1 hour | 191.5 U/L |
| Severe Renal Impairment | Levels of cCK18 | 8 hours | 212.0 U/L |
| Severe Renal Impairment | Levels of cCK18 | 2 hours | 198.0 U/L |
| Severe Renal Impairment | Levels of cCK18 | 24 hours | 192.5 U/L |
| Severe Renal Impairment | Levels of cCK18 | 3 hours | 201.0 U/L |