Hepatic Insufficiency
Conditions
Brief summary
The purpose of this study is to assess the effects of hepatic impairment on the single dose pharmacokinetics of BMS-790052.
Interventions
DRUGBMS-790052
Capsules, Oral, 30 mg, single dose, one day
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: * Male and female subjects aged 18 to 70 years, with hepatic impairment conforming to Child-Pugh class A, B or C * Healthy subjects to the extent possible matched to the first four hepatically impaired subject in each Child-Pugh class with regard to age (approximately ± 10 years), body weight (approximately ± 20%) and gender Key
Exclusion criteria
* History of esophageal and gastric variceal bleeding within past 6 months * Primarily cholestatic liver diseases * Active alcoholic hepatitis * Stable encephalopathy of \>= Stage 2 * Presence of severe ascites or edema * Presence of hepatopulmonary or hepatorenal syndrome * Positive for HCV, unless HCV RNA is undetectable
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Apparent Volume of Distribution at Steady State (Vss/F) | Pre-dose (0), 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48, 72 hours post-dose (both healthy and hepatically impaired participants) and 96 hours post-dose (only for hepatically impaired participants) | Apparent volume of distribution was calculated by dividing the product of the dose and mean residence time (MRT) by AUC(INF). AUC(INF) was estimated as AUC(0-T) + Ct/λ z, where λ z was the terminal elimination rate constant and Ct was the last observable concentration. |
| Maximum Observed Plasma Concentration (Cmax) of BMS-790052 | Pre-dose (0), 0.5,1, 1.5, 2, 4, 8, 12, 24, 48, 72 hours post-dose (both healthy and hepatically impaired participants) and 96 hours post-dose (only for hepatically impaired participants) | Maximum observed plasma concentration following drug administration from the raw plasma concentration-time data. The plasma samples were analysed for BMS-790052 by using a validated liquid chromatography tandem mass spectrometric (LC-MS/MS) assay. |
| Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Last Measurable Concentration [AUC(0-T)] of BMS-790052 | Pre-dose (0), 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48, 72 hours post-dose (both healthy and hepatically impaired participants) and 96 hours post-dose (only for hepatically impaired participants) | AUC(0-T) was calculated by the sum of linear trapezoids using non-compartmental analysis. |
| Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of BMS-790052 | Pre-dose (0), 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48, 72 hours post-dose (both healthy and hepatically impaired participants) and 96 hours post-dose (only for hepatically impaired participants) | AUC(INF) was estimated as AUC(0-T) + Ct/λ z, where λ z was the terminal elimination rate constant and Ct was the last observable concentration. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of BMS-790052 | Pre-dose (0), 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48, 72 hours post-dose (both healthy and hepatically impaired participants) and 96 hours post-dose (only for hepatically impaired participants) | Tmax was defined as the time required to reach maximum observed plasma concentration. Tmax was directly determined from the raw plasma concentration-time data. |
| Terminal Half-life (T-HALF) of BMS-790052 | Pre-dose (0), 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48, 72 hours post-dose (both healthy and hepatically impaired participants) and 96 hours post-dose (only for hepatically impaired participants) | Terminal half-life was the time required for one half of the total amount of administered drug eliminated from the body. |
| Apparent Total Body Clearance (CLT/F) of BMS-790052 | Pre-dose (0), 0.5,1, 1.5, 2, 4, 8, 12, 24, 48, 72 hours post-dose (both healthy and hepatically impaired participants) and 96 hours post-dose (only for hepatically impaired participants) | Apparent total body clearance was calculated as dose/AUC(INF). AUC(INF) was estimated as AUC(0-T) + Ct/λ z, where λ z was the terminal elimination rate constant and Ct was the last observable concentration. |
| Apparent Clearance of Free BMS-790052 (CLu/F) | Pre-dose (0), 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48, 72 hours post-dose (both healthy and hepatically impaired participants) and 96 hours post-dose (only for hepatically impaired participants) | CLu/F was calculated by dividing the apparent total body clearance (CLT/F) by mean fraction of unbound drug (fu) for both (1 hour and 4 hour post dose) time points combined. Apparent total body clearance was calculated as dose/AUC(INF). AUC(INF) was estimated as AUC(0-T) + Ct/ λz, where λz was the terminal elimination rate constant and Ct was the last observable concentration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died | Day 1 to end of study for AEs and, Day 1 to up to 30 days after last dose for SAE. | AE was defined as any new unfavorable symptom, sign, or disease or worsening of a pre-existing condition that does not necessarily have a causal relationship with treatment. SAE was defined as a medical event that at any dose resulted in death, persistent or significant disability/incapacity, or drug dependency/abuse; was life-threatening, an important medical event, or a congenital anomaly/birth defect; or required or prolonged hospitalization. Study Discharge (end of study) was Day 4 (healthy participants) or Day 5 (hepatically impaired participants). |
Countries
United States
Participant flow
Pre-assignment details
A total of 46 participants were enrolled in the study, of which 30 participants were treated with study drug and 16 participants were not treated with study drug as they no longer met study criteria.
Participants by arm
| Arm | Count |
|---|---|
| Child Pugh Class-A Participants with mild liver damage were administered with single oral dose of 30 mg (3 x 10 mg capsules) of BMS-790052 after 10 hours overnight fasting. | 6 |
| Child Pugh Class-B Participants with moderate liver damage were administered with single oral dose of 30 mg (3 x 10 mg capsules) of BMS-790052 after 10 hours overnight fasting. | 6 |
| Child Pugh Class-C Participants with severe liver damage were administered with single oral dose of 30 mg (3 x 10 mg capsules) of BMS-790052 after 10 hours overnight fasting. | 6 |
| Healthy Participants Healthy participants were administered with single oral dose of 30 mg (3 x 10 mg capsules) of BMS-790052 after 10 hours overnight fasting. | 12 |
| Total | 30 |
Baseline characteristics
| Characteristic | Child Pugh Class-A | Child Pugh Class-B | Child Pugh Class-C | Healthy Participants | Total |
|---|---|---|---|---|---|
| Age, Customized < 65 years | 6 participants | 5 participants | 5 participants | 12 participants | 28 participants |
| Age, Customized >= 65 years | 0 participants | 1 participants | 1 participants | 0 participants | 2 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 2 Participants | 5 Participants | 12 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 4 Participants | 7 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 6 | 3 / 6 | 2 / 6 | 2 / 12 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 12 |
Outcome results
Primary
Apparent Clearance of Free BMS-790052 (CLu/F)
CLu/F was calculated by dividing the apparent total body clearance (CLT/F) by mean fraction of unbound drug (fu) for both (1 hour and 4 hour post dose) time points combined. Apparent total body clearance was calculated as dose/AUC(INF). AUC(INF) was estimated as AUC(0-T) + Ct/ λz, where λz was the terminal elimination rate constant and Ct was the last observable concentration.
Time frame: Pre-dose (0), 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48, 72 hours post-dose (both healthy and hepatically impaired participants) and 96 hours post-dose (only for hepatically impaired participants)
Population: Analysis was performed in PK population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Child Pugh Class-A | Apparent Clearance of Free BMS-790052 (CLu/F) | 19529 mL/min | Geometric Coefficient of Variation 66 |
| Child Pugh Class-B | Apparent Clearance of Free BMS-790052 (CLu/F) | 12028 mL/min | Geometric Coefficient of Variation 52 |
| Child Pugh Class-C | Apparent Clearance of Free BMS-790052 (CLu/F) | 12468 mL/min | Geometric Coefficient of Variation 61 |
| Healthy Participants | Apparent Clearance of Free BMS-790052 (CLu/F) | 11796 mL/min | Geometric Coefficient of Variation 33 |
Primary
Apparent Total Body Clearance (CLT/F) of BMS-790052
Apparent total body clearance was calculated as dose/AUC(INF). AUC(INF) was estimated as AUC(0-T) + Ct/λ z, where λ z was the terminal elimination rate constant and Ct was the last observable concentration.
Time frame: Pre-dose (0), 0.5,1, 1.5, 2, 4, 8, 12, 24, 48, 72 hours post-dose (both healthy and hepatically impaired participants) and 96 hours post-dose (only for hepatically impaired participants)
Population: Analysis was performed in PK set population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Child Pugh Class-A | Apparent Total Body Clearance (CLT/F) of BMS-790052 | 120 milliliter/minute (mL/min) | Geometric Coefficient of Variation 85 |
| Child Pugh Class-B | Apparent Total Body Clearance (CLT/F) of BMS-790052 | 110 milliliter/minute (mL/min) | Geometric Coefficient of Variation 47 |
| Child Pugh Class-C | Apparent Total Body Clearance (CLT/F) of BMS-790052 | 108 milliliter/minute (mL/min) | Geometric Coefficient of Variation 78 |
| Healthy Participants | Apparent Total Body Clearance (CLT/F) of BMS-790052 | 69 milliliter/minute (mL/min) | Geometric Coefficient of Variation 29 |
Primary
Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Last Measurable Concentration [AUC(0-T)] of BMS-790052
AUC(0-T) was calculated by the sum of linear trapezoids using non-compartmental analysis.
Time frame: Pre-dose (0), 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48, 72 hours post-dose (both healthy and hepatically impaired participants) and 96 hours post-dose (only for hepatically impaired participants)
Population: Analysis was performed in the Pharmacokinetic population (all participants who received study drug and had adequate PK profiles).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Child Pugh Class-A | Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Last Measurable Concentration [AUC(0-T)] of BMS-790052 | 4151 ng*hour (h)/mL | Geometric Coefficient of Variation 43 |
| Child Pugh Class-B | Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Last Measurable Concentration [AUC(0-T)] of BMS-790052 | 4490 ng*hour (h)/mL | Geometric Coefficient of Variation 38 |
| Child Pugh Class-C | Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Last Measurable Concentration [AUC(0-T)] of BMS-790052 | 4534 ng*hour (h)/mL | Geometric Coefficient of Variation 74 |
| Healthy Participants | Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Last Measurable Concentration [AUC(0-T)] of BMS-790052 | 7165 ng*hour (h)/mL | Geometric Coefficient of Variation 24 |
Primary
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of BMS-790052
AUC(INF) was estimated as AUC(0-T) + Ct/λ z, where λ z was the terminal elimination rate constant and Ct was the last observable concentration.
Time frame: Pre-dose (0), 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48, 72 hours post-dose (both healthy and hepatically impaired participants) and 96 hours post-dose (only for hepatically impaired participants)
Population: Analysis was performed in the Pharmacokinetic population (all participants who received study drug and had adequate PK profiles).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Child Pugh Class-A | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of BMS-790052 | 4174 ng* h/mL | Geometric Coefficient of Variation 43 |
| Child Pugh Class-B | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of BMS-790052 | 4550 ng* h/mL | Geometric Coefficient of Variation 39 |
| Child Pugh Class-C | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of BMS-790052 | 4649 ng* h/mL | Geometric Coefficient of Variation 78 |
| Healthy Participants | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of BMS-790052 | 7286 ng* h/mL | Geometric Coefficient of Variation 25 |
Primary
Maximum Observed Plasma Concentration (Cmax) of BMS-790052
Maximum observed plasma concentration following drug administration from the raw plasma concentration-time data. The plasma samples were analysed for BMS-790052 by using a validated liquid chromatography tandem mass spectrometric (LC-MS/MS) assay.
Time frame: Pre-dose (0), 0.5,1, 1.5, 2, 4, 8, 12, 24, 48, 72 hours post-dose (both healthy and hepatically impaired participants) and 96 hours post-dose (only for hepatically impaired participants)
Population: Analysis was performed in the Pharmacokinetic population (all participants who received study drug and had adequate PK profiles).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Child Pugh Class-A | Maximum Observed Plasma Concentration (Cmax) of BMS-790052 | 380 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 44 |
| Child Pugh Class-B | Maximum Observed Plasma Concentration (Cmax) of BMS-790052 | 382 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 23 |
| Child Pugh Class-C | Maximum Observed Plasma Concentration (Cmax) of BMS-790052 | 317 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 65 |
| Healthy Participants | Maximum Observed Plasma Concentration (Cmax) of BMS-790052 | 698 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 30 |
Primary
Terminal Half-life (T-HALF) of BMS-790052
Terminal half-life was the time required for one half of the total amount of administered drug eliminated from the body.
Time frame: Pre-dose (0), 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48, 72 hours post-dose (both healthy and hepatically impaired participants) and 96 hours post-dose (only for hepatically impaired participants)
Population: Analysis was performed in the Pharmacokinetic population (all participants who received study drug and had adequate PK profiles).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Child Pugh Class-A | Terminal Half-life (T-HALF) of BMS-790052 | 12.3 hours | Standard Deviation 2.49 |
| Child Pugh Class-B | Terminal Half-life (T-HALF) of BMS-790052 | 15.0 hours | Standard Deviation 4.59 |
| Child Pugh Class-C | Terminal Half-life (T-HALF) of BMS-790052 | 17.2 hours | Standard Deviation 10.55 |
| Healthy Participants | Terminal Half-life (T-HALF) of BMS-790052 | 12.4 hours | Standard Deviation 2.23 |
Primary
The Apparent Volume of Distribution at Steady State (Vss/F)
Apparent volume of distribution was calculated by dividing the product of the dose and mean residence time (MRT) by AUC(INF). AUC(INF) was estimated as AUC(0-T) + Ct/λ z, where λ z was the terminal elimination rate constant and Ct was the last observable concentration.
Time frame: Pre-dose (0), 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48, 72 hours post-dose (both healthy and hepatically impaired participants) and 96 hours post-dose (only for hepatically impaired participants)
Population: Analysis was performed in PK population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Child Pugh Class-A | The Apparent Volume of Distribution at Steady State (Vss/F) | 98557 mL | Geometric Coefficient of Variation 67 |
| Child Pugh Class-B | The Apparent Volume of Distribution at Steady State (Vss/F) | 111612 mL | Geometric Coefficient of Variation 24 |
| Child Pugh Class-C | The Apparent Volume of Distribution at Steady State (Vss/F) | 123034 mL | Geometric Coefficient of Variation 56 |
| Healthy Participants | The Apparent Volume of Distribution at Steady State (Vss/F) | 61250 mL | Geometric Coefficient of Variation 19 |
Primary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of BMS-790052
Tmax was defined as the time required to reach maximum observed plasma concentration. Tmax was directly determined from the raw plasma concentration-time data.
Time frame: Pre-dose (0), 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48, 72 hours post-dose (both healthy and hepatically impaired participants) and 96 hours post-dose (only for hepatically impaired participants)
Population: Analysis was performed in the Pharmacokinetic population (all participants who received study drug and had adequate PK profiles).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Child Pugh Class-A | Time to Reach Maximum Observed Plasma Concentration (Tmax) of BMS-790052 | 1.5 hours |
| Child Pugh Class-B | Time to Reach Maximum Observed Plasma Concentration (Tmax) of BMS-790052 | 1.0 hours |
| Child Pugh Class-C | Time to Reach Maximum Observed Plasma Concentration (Tmax) of BMS-790052 | 1.5 hours |
| Healthy Participants | Time to Reach Maximum Observed Plasma Concentration (Tmax) of BMS-790052 | 1.3 hours |
Secondary
Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died
AE was defined as any new unfavorable symptom, sign, or disease or worsening of a pre-existing condition that does not necessarily have a causal relationship with treatment. SAE was defined as a medical event that at any dose resulted in death, persistent or significant disability/incapacity, or drug dependency/abuse; was life-threatening, an important medical event, or a congenital anomaly/birth defect; or required or prolonged hospitalization. Study Discharge (end of study) was Day 4 (healthy participants) or Day 5 (hepatically impaired participants).
Time frame: Day 1 to end of study for AEs and, Day 1 to up to 30 days after last dose for SAE.
Population: Analysis was done in safety population, defined as all the participants who received study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Child Pugh Class-A | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died | Discontinuations due to AEs | 0 Participants |
| Child Pugh Class-A | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died | Death | 0 Participants |
| Child Pugh Class-A | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died | SAEs | 0 Participants |
| Child Pugh Class-B | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died | Discontinuations due to AEs | 0 Participants |
| Child Pugh Class-B | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died | SAEs | 0 Participants |
| Child Pugh Class-B | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died | Death | 0 Participants |
| Child Pugh Class-C | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died | SAEs | 0 Participants |
| Child Pugh Class-C | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died | Discontinuations due to AEs | 0 Participants |
| Child Pugh Class-C | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died | Death | 0 Participants |
| Healthy Participants | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died | Death | 0 Participants |
| Healthy Participants | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died | Discontinuations due to AEs | 0 Participants |
| Healthy Participants | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died | SAEs | 0 Participants |