Hepatitis C
Conditions
Brief summary
The purpose of this study is to assess the effect of renal function impairment on the single dose pharmacokinetics of Daclatasvir.
Detailed description
Treatment, Parallel Assignment, Open Label, Non-Randomized, Single Dose Adaptive Design, Pharmacokinetics Study
Interventions
DRUGDaclatasvir
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
\- Meet renal function criteria in one of four categories
Exclusion criteria
\- Unstable or uncontrolled medical conditions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Daclatasvir | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | AUC(INF) was estimated by summing the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration and the extrapolated area, computed by the quotient of the last observable concentration and elimination rate constant. The pharmacokinetic (PK) analysis was based on Cockcroft-Gault (C-G) creatinine clearance (CLcr) grouping method: normal renal function, end stage renal disease (ESRD), moderate and severe renal impairment. Mild participants were counted as per their original allocation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Daclatasvir | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | Maximum observed plasma concentration following drug administration from the raw plasma concentration-time data. The plasma samples were analyzed for daclatasvir by using a validated liquid chromatography tandem mass spectrometric (LC-MS/MS) assay. |
| Unbound Maximum Observed Plasma Concentrations of Daclatasvir | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | Unbound Maximum observed plasma concentrations (Cmaxu) was calculated by multiplying maximum observed plasma concentrations by mean fraction of unbound drug from 1 hour post-dose time point. |
| Area Under the Plasma Concentration-time Curve From Time Zero to Last Measurable Concentration [AUC(0-T)] of Daclatasvir | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | AUC(0-T) was calculated as the sum of linear trapezoids using non-compartmental analysis. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Daclatasvir | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | Tmax was defined as the time required to reach maximum observed plasma concentration. Tmax was directly determined from the raw plasma concentration-time data. |
| Plasma Half-life (T-half) of Daclatasvir | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | 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 Daclatasvir | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | Apparent total body clearance was calculated by dividing the dose by area under the plasma concentration-time curve from time zero extrapolated to infinite time. |
| Unbound Apparent Clearance (CLU/F) of Daclatasvir | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | The CLU/F was calculated by dividing the apparent total body clearance by mean fraction of unbound drug from 1 hour post dose time point. |
| Unbound Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity Time (AUC(INF)u) of Daclatasvir | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | AUC(INF)u was calculated by multiplying the area under the plasma concentration-time curve from time zero extrapolated to infinite time by mean fraction of unbound drug from 1 hour post-dose time point. |
| Renal Clearance (CLR) of Daclatasvir | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | The CLR was calculated by dividing the total amount excreted in the urine from 0 to 96 hours by the area under the plasma concentration-time curve from time zero extrapolated to infinite time. |
| Apparent Volume of Distribution (Vd/F) of Daclatasvir | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | The Vd/F was calculated by dividing the product of the dose and mean residence time by area under the plasma concentration-time curve from time zero extrapolated to infinite time. |
| Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events and Who Died | First dose up to Day 5 post last dose for AEs; up to 30 days post last dose for SAEs | Adverse event (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 hospitalisation. |
| Number of Participants With Clinically Significant Laboratory Marked Abnormalities Reported as Adverse Events | Baseline up to Day 5 post dose | Significant laboratory abnormalities were defined as any test results which were observed beyond the clinically acceptable limits as per the discretion of investigator. |
| Number of Participants With Clinically Relevant Changes in Electrocardiogram (ECG) Reported as Adverse Events | Baseline up to Day 5 post dose | The number of participants with clinically relevant changes in ECG which were considered as adverse events was determined. |
| Number of Participants With Out-of-range Vital Signs Reported as Adverse Events | Baseline up to Day 5 post dose | The total number of participants with abnormal range vital signs which were considered as adverse events was determined. |
| Percent Urinary Recovery (%UR) of Daclatasvir | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | The percentage of daclatasvir recovered in the urine was determined by using validated liquid chromatography-tandem mass spectrometry methods. The sum of the percentage of dose recovered in urine from all intervals was calculated to obtain the total percentage of urinary excretion. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 2 centers in United States of America.
Pre-assignment details
A total of 58 participants were enrolled and 36 were treated with study drug. Remaining 22 were not treated (14 no longer met study criteria, 4 other reasons, 2 administrative reasons and 2 withdrew consent). Participants were grouped by Cockcroft-Gault creatine clearance method for primary analysis.
Participants by arm
| Arm | Count |
|---|---|
| Normal Renal Function/Mild Renal Impairment Participants with normal renal function and had creatinine clearance by the Cockcroft-Gault method \>=90 milliliter per minute were administered with single oral dose of daclatasvir 60 mg tablet after 10 hours of overnight fasting on Day 1. One participant from this group, who had eGFR 60-89 mL/min per 1.73 m\^2, was reallocated into mild renal impairment reporting arm and was administered with a single oral dose of daclatasvir 60 mg tablet after 10 hours of overnight fasting on Day 1. Original allocation was based on an estimated eGFR, while the reallocation was based on the eGFR measurement at baseline. | 12 |
| Mild/Moderate Renal Impairment Participants with moderate renal impairment and had eGFR 30-59 mL/min per 1.73 m\^2 were administered with single oral dose of daclatasvir 60 mg tablet after 10 hours of overnight fasting on Day 1. Two participants from this group, who had eGFR 60-89 mL/min per 1.73 m\^2, were reallocated into mild renal impairment reporting arm and were administered with a single oral dose of daclatasvir 60 mg tablet after 10 hours of overnight fasting on Day 1. Original allocation was based on an estimated eGFR, while the reallocation was based on the eGFR measurement at baseline. | 6 |
| Mild/Severe Renal Impairment Participants with severe renal impairment and had eGFR 15 to 29 mL/min per 1.73 m\^2 were administered with single oral dose of daclatasvir 60 mg tablet after 10 hours of overnight fasting on Day 1. One participant from this group, who had eGFR 60-89 mL/min per 1.73 m\^2, was reallocated into mild renal impairment reporting arm and was administered with a single oral dose of daclatasvir 60 mg tablet after 10 hours of overnight fasting on Day 1. Original allocation was based on an estimated eGFR, while the reallocation was based on the eGFR measurement at baseline. | 6 |
| End Stage Renal Disease Participants with end stage renal disease and had eGFR \<15 mL/ min per 1.73 m\^2, with or without hemodialysis were administered with single oral dose of daclatasvir 60 mg tablet after 10 hours of overnight fasting on Day 1. | 12 |
| Total | 36 |
Baseline characteristics
| Characteristic | Normal Renal Function/Mild Renal Impairment | Mild/Moderate Renal Impairment | Mild/Severe Renal Impairment | End Stage Renal Disease | Total |
|---|---|---|---|---|---|
| Age, Continuous | 48.6 years STANDARD_DEVIATION 8.5 | 62.0 years STANDARD_DEVIATION 12.6 | 66.3 years STANDARD_DEVIATION 9.9 | 49.0 years STANDARD_DEVIATION 11.7 | 53.9 years STANDARD_DEVIATION 12.6 |
| Region of Enrollment United States | 12 participants | 6 participants | 6 participants | 12 participants | 36 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 2 Participants | 1 Participants | 6 Participants |
| Sex: Female, Male Male | 11 Participants | 4 Participants | 4 Participants | 11 Participants | 30 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 | 0 / 12 | 1 / 6 | 1 / 6 | 3 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 6 | 0 / 6 | 0 / 12 |
Outcome results
Primary
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Daclatasvir
AUC(INF) was estimated by summing the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration and the extrapolated area, computed by the quotient of the last observable concentration and elimination rate constant. The pharmacokinetic (PK) analysis was based on Cockcroft-Gault (C-G) creatinine clearance (CLcr) grouping method: normal renal function, end stage renal disease (ESRD), moderate and severe renal impairment. Mild participants were counted as per their original allocation.
Time frame: Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose
Population: PK data set included all participants who received at least 1 dose of daclatasvir with adequate PK profiles. The PK analysis was based on the C-G CLcr grouping method: normal renal function (n=11), ESRD (n=10), moderate (n=5) and severe renal impairment (n=6). Mild participants (n=4) are also counted as per their original allocation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Daclatasvir | 11215.264 nanograms*hours/milliliter (ng*h/mL) | Geometric Coefficient of Variation 40 |
| Mild Renal Impairment | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Daclatasvir | 21261.199 nanograms*hours/milliliter (ng*h/mL) | Geometric Coefficient of Variation 62 |
| Moderate Renal Impairment | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Daclatasvir | 24789.951 nanograms*hours/milliliter (ng*h/mL) | Geometric Coefficient of Variation 35 |
| Severe Renal Impairment | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Daclatasvir | 21946.450 nanograms*hours/milliliter (ng*h/mL) | Geometric Coefficient of Variation 39 |
| End Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Daclatasvir | 14257.489 nanograms*hours/milliliter (ng*h/mL) | Geometric Coefficient of Variation 25 |
Secondary
Apparent Total Body Clearance (CLT/F) of Daclatasvir
Apparent total body clearance was calculated by dividing the dose by area under the plasma concentration-time curve from time zero extrapolated to infinite time.
Time frame: Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose
Population: Pharmacokinetic (PK) data set included all participants who received at least 1 dose of daclatasvir with adequate PK profiles. The PK analysis was based on C-G CLcr grouping method: normal renal function (n=11), ESRD (n=10), moderate (n=5) and severe renal impairment (n=6). Mild participants (n=4) are also counted as per their original allocation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Apparent Total Body Clearance (CLT/F) of Daclatasvir | 89.164 milliliter/minute (mL/min) | Geometric Coefficient of Variation 26 |
| Mild Renal Impairment | Apparent Total Body Clearance (CLT/F) of Daclatasvir | 47.034 milliliter/minute (mL/min) | Geometric Coefficient of Variation 43 |
| Moderate Renal Impairment | Apparent Total Body Clearance (CLT/F) of Daclatasvir | 40.339 milliliter/minute (mL/min) | Geometric Coefficient of Variation 27 |
| Severe Renal Impairment | Apparent Total Body Clearance (CLT/F) of Daclatasvir | 45.565 milliliter/minute (mL/min) | Geometric Coefficient of Variation 31 |
| End Stage Renal Disease | Apparent Total Body Clearance (CLT/F) of Daclatasvir | 70.139 milliliter/minute (mL/min) | Geometric Coefficient of Variation 33 |
Secondary
Apparent Volume of Distribution (Vd/F) of Daclatasvir
The Vd/F was calculated by dividing the product of the dose and mean residence time by area under the plasma concentration-time curve from time zero extrapolated to infinite time.
Time frame: Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose
Population: Pharmacokinetic (PK) data set included all participants who received at least 1 dose of daclatasvir with adequate PK profiles. The PK analysis was based on C-G CLcr grouping method: normal renal function (n=11), ESRD (n=10), moderate (n=5) and severe renal impairment (n=6). Mild participants (n=4) are also counted as per their original allocation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Apparent Volume of Distribution (Vd/F) of Daclatasvir | 105.157 Liters | Geometric Coefficient of Variation 37 |
| Mild Renal Impairment | Apparent Volume of Distribution (Vd/F) of Daclatasvir | 63.761 Liters | Geometric Coefficient of Variation 30 |
| Moderate Renal Impairment | Apparent Volume of Distribution (Vd/F) of Daclatasvir | 59.054 Liters | Geometric Coefficient of Variation 36 |
| Severe Renal Impairment | Apparent Volume of Distribution (Vd/F) of Daclatasvir | 79.769 Liters | Geometric Coefficient of Variation 35 |
| End Stage Renal Disease | Apparent Volume of Distribution (Vd/F) of Daclatasvir | 95.186 Liters | Geometric Coefficient of Variation 37 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to Last Measurable Concentration [AUC(0-T)] of Daclatasvir
AUC(0-T) was calculated as the sum of linear trapezoids using non-compartmental analysis.
Time frame: Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose
Population: Pharmacokinetic (PK) data set included all participants who received at least 1 dose of daclatasvir with adequate PK profiles. The analysis was based on C-G CLcr grouping method: normal renal function (n=11), ESRD (n=10), moderate (n=5) and severe renal impairment (n=6). Mild participants (n=4) are also counted as per their original allocation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Area Under the Plasma Concentration-time Curve From Time Zero to Last Measurable Concentration [AUC(0-T)] of Daclatasvir | 11092.967 ng*hour (h)/mL | Geometric Coefficient of Variation 40 |
| Mild Renal Impairment | Area Under the Plasma Concentration-time Curve From Time Zero to Last Measurable Concentration [AUC(0-T)] of Daclatasvir | 20852.129 ng*hour (h)/mL | Geometric Coefficient of Variation 60 |
| Moderate Renal Impairment | Area Under the Plasma Concentration-time Curve From Time Zero to Last Measurable Concentration [AUC(0-T)] of Daclatasvir | 24343.711 ng*hour (h)/mL | Geometric Coefficient of Variation 36 |
| Severe Renal Impairment | Area Under the Plasma Concentration-time Curve From Time Zero to Last Measurable Concentration [AUC(0-T)] of Daclatasvir | 21238.909 ng*hour (h)/mL | Geometric Coefficient of Variation 37 |
| End Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time Zero to Last Measurable Concentration [AUC(0-T)] of Daclatasvir | 13934.562 ng*hour (h)/mL | Geometric Coefficient of Variation 25 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Daclatasvir
Maximum observed plasma concentration following drug administration from the raw plasma concentration-time data. The plasma samples were analyzed for daclatasvir by using a validated liquid chromatography tandem mass spectrometric (LC-MS/MS) assay.
Time frame: Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose
Population: Pharmacokinetic (PK) data set included all participants who received at least 1 dose of daclatasvir with adequate PK profiles. The PK analysis was based on C-G CLcr grouping method: normal renal function (n=11), ESRD (n=10), moderate (n=5) and severe renal impairment (n=6). Mild participants (n=4) are also counted as per their original allocation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Maximum Observed Plasma Concentration (Cmax) of Daclatasvir | 1111.497 ng/mL | Geometric Coefficient of Variation 39 |
| Mild Renal Impairment | Maximum Observed Plasma Concentration (Cmax) of Daclatasvir | 1619.572 ng/mL | Geometric Coefficient of Variation 13 |
| Moderate Renal Impairment | Maximum Observed Plasma Concentration (Cmax) of Daclatasvir | 1745.845 ng/mL | Geometric Coefficient of Variation 31 |
| Severe Renal Impairment | Maximum Observed Plasma Concentration (Cmax) of Daclatasvir | 1207.137 ng/mL | Geometric Coefficient of Variation 33 |
| End Stage Renal Disease | Maximum Observed Plasma Concentration (Cmax) of Daclatasvir | 1085.344 ng/mL | Geometric Coefficient of Variation 15 |
Secondary
Number of Participants With Clinically Relevant Changes in Electrocardiogram (ECG) Reported as Adverse Events
The number of participants with clinically relevant changes in ECG which were considered as adverse events was determined.
Time frame: Baseline up to Day 5 post dose
Population: Analysis was done in safety data set population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Normal Renal Function | Number of Participants With Clinically Relevant Changes in Electrocardiogram (ECG) Reported as Adverse Events | 0 Participants |
| Mild Renal Impairment | Number of Participants With Clinically Relevant Changes in Electrocardiogram (ECG) Reported as Adverse Events | 0 Participants |
| Moderate Renal Impairment | Number of Participants With Clinically Relevant Changes in Electrocardiogram (ECG) Reported as Adverse Events | 0 Participants |
| Severe Renal Impairment | Number of Participants With Clinically Relevant Changes in Electrocardiogram (ECG) Reported as Adverse Events | 0 Participants |
Secondary
Number of Participants With Clinically Significant Laboratory Marked Abnormalities Reported as Adverse Events
Significant laboratory abnormalities were defined as any test results which were observed beyond the clinically acceptable limits as per the discretion of investigator.
Time frame: Baseline up to Day 5 post dose
Population: The analysis was done in safety population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Normal Renal Function | Number of Participants With Clinically Significant Laboratory Marked Abnormalities Reported as Adverse Events | 0 Participants |
| Mild Renal Impairment | Number of Participants With Clinically Significant Laboratory Marked Abnormalities Reported as Adverse Events | 0 Participants |
| Moderate Renal Impairment | Number of Participants With Clinically Significant Laboratory Marked Abnormalities Reported as Adverse Events | 0 Participants |
| Severe Renal Impairment | Number of Participants With Clinically Significant Laboratory Marked Abnormalities Reported as Adverse Events | 0 Participants |
Secondary
Number of Participants With Out-of-range Vital Signs Reported as Adverse Events
The total number of participants with abnormal range vital signs which were considered as adverse events was determined.
Time frame: Baseline up to Day 5 post dose
Population: Analysis was done in safety data set population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Normal Renal Function | Number of Participants With Out-of-range Vital Signs Reported as Adverse Events | 0 Participants |
| Mild Renal Impairment | Number of Participants With Out-of-range Vital Signs Reported as Adverse Events | 0 Participants |
| Moderate Renal Impairment | Number of Participants With Out-of-range Vital Signs Reported as Adverse Events | 0 Participants |
| Severe Renal Impairment | Number of Participants With Out-of-range Vital Signs Reported as Adverse Events | 1 Participants |
Secondary
Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events and Who Died
Adverse event (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 hospitalisation.
Time frame: First dose up to Day 5 post last dose for AEs; up to 30 days post last dose for SAEs
Population: Analysis was done in safety data set population, defined as all the participants who received the study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Normal Renal Function | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events and Who Died | Discontinuations due to AEs | 0 Participants |
| Normal Renal Function | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events and Who Died | SAEs | 0 Participants |
| Normal Renal Function | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events and Who Died | Death | 0 Participants |
| Mild Renal Impairment | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events and Who Died | Discontinuations due to AEs | 0 Participants |
| Mild Renal Impairment | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events and Who Died | Death | 0 Participants |
| Mild Renal Impairment | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events and Who Died | SAEs | 0 Participants |
| Moderate Renal Impairment | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events and Who Died | SAEs | 0 Participants |
| Moderate Renal Impairment | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events and Who Died | Death | 0 Participants |
| Moderate Renal Impairment | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events and Who Died | Discontinuations due to AEs | 0 Participants |
| Severe Renal Impairment | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events and Who Died | Discontinuations due to AEs | 0 Participants |
| Severe Renal Impairment | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events and Who Died | SAEs | 0 Participants |
| Severe Renal Impairment | Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events and Who Died | Death | 0 Participants |
Secondary
Percent Urinary Recovery (%UR) of Daclatasvir
The percentage of daclatasvir recovered in the urine was determined by using validated liquid chromatography-tandem mass spectrometry methods. The sum of the percentage of dose recovered in urine from all intervals was calculated to obtain the total percentage of urinary excretion.
Time frame: Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose
Population: Pharmacokinetic (PK) data set included all participants who received at least 1 dose of daclatasvir with adequate PK profiles. The PK analysis was based on C-G CLcr grouping method: normal renal function (n=11), ESRD (n=3), moderate (n=5) and severe renal impairment (n=5). Mild participants (n=4) are also counted as per their original allocation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Percent Urinary Recovery (%UR) of Daclatasvir | 5.007 Percentage of daclatasvir recovered | Geometric Coefficient of Variation 36 |
| Mild Renal Impairment | Percent Urinary Recovery (%UR) of Daclatasvir | 5.820 Percentage of daclatasvir recovered | Geometric Coefficient of Variation 27 |
| Moderate Renal Impairment | Percent Urinary Recovery (%UR) of Daclatasvir | 3.530 Percentage of daclatasvir recovered | Geometric Coefficient of Variation 40 |
| Severe Renal Impairment | Percent Urinary Recovery (%UR) of Daclatasvir | 2.658 Percentage of daclatasvir recovered | Geometric Coefficient of Variation 58 |
| End Stage Renal Disease | Percent Urinary Recovery (%UR) of Daclatasvir | 0.199 Percentage of daclatasvir recovered | Geometric Coefficient of Variation 131 |
Secondary
Plasma Half-life (T-half) of Daclatasvir
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, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose
Population: Pharmacokinetic (PK) data set included all participants who received at least 1 dose of daclatasvir with adequate PK profiles. The PK analysis was based on C-G CLcr grouping method: normal renal function (n=11), ESRD (n=10), moderate (n=5) and severe renal impairment (n=6). Mild participants (n=4) are also counted as per their original allocation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Plasma Half-life (T-half) of Daclatasvir | 13.625 hours | Geometric Coefficient of Variation 25 |
| Mild Renal Impairment | Plasma Half-life (T-half) of Daclatasvir | 15.661 hours | Geometric Coefficient of Variation 31 |
| Moderate Renal Impairment | Plasma Half-life (T-half) of Daclatasvir | 16.912 hours | Geometric Coefficient of Variation 19 |
| Severe Renal Impairment | Plasma Half-life (T-half) of Daclatasvir | 20.224 hours | Geometric Coefficient of Variation 24 |
| End Stage Renal Disease | Plasma Half-life (T-half) of Daclatasvir | 15.678 hours | Geometric Coefficient of Variation 37 |
Secondary
Renal Clearance (CLR) of Daclatasvir
The CLR was calculated by dividing the total amount excreted in the urine from 0 to 96 hours by the area under the plasma concentration-time curve from time zero extrapolated to infinite time.
Time frame: Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose
Population: Pharmacokinetic (PK) data set included all participants who received at least 1 dose of daclatasvir with adequate PK profiles. The PK analysis was based on C-G CLcr grouping method: normal renal function (n=11), ESRD (n=3), moderate (n=5) and severe renal impairment (n=5). Mild participants (n=4) are also counted as per their original allocation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Renal Clearance (CLR) of Daclatasvir | 4.465 mL/min | Geometric Coefficient of Variation 29 |
| Mild Renal Impairment | Renal Clearance (CLR) of Daclatasvir | 2.737 mL/min | Geometric Coefficient of Variation 28 |
| Moderate Renal Impairment | Renal Clearance (CLR) of Daclatasvir | 1.424 mL/min | Geometric Coefficient of Variation 48 |
| Severe Renal Impairment | Renal Clearance (CLR) of Daclatasvir | 1.165 mL/min | Geometric Coefficient of Variation 37 |
| End Stage Renal Disease | Renal Clearance (CLR) of Daclatasvir | 0.147 mL/min | Geometric Coefficient of Variation 114 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Daclatasvir
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, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose
Population: Pharmacokinetic (PK) data set included all participants who received at least 1 dose of daclatasvir with adequate PK profiles. The PK analysis was based on C-G CLcr grouping method: normal renal function (n=11), ESRD (n=10), moderate (n=5) and severe renal impairment (n=6). Mild participants (n=4) are also counted as per their original allocation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normal Renal Function | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Daclatasvir | 1.000 hours |
| Mild Renal Impairment | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Daclatasvir | 1.250 hours |
| Moderate Renal Impairment | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Daclatasvir | 1.000 hours |
| Severe Renal Impairment | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Daclatasvir | 1.500 hours |
| End Stage Renal Disease | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Daclatasvir | 1.250 hours |
Secondary
Unbound Apparent Clearance (CLU/F) of Daclatasvir
The CLU/F was calculated by dividing the apparent total body clearance by mean fraction of unbound drug from 1 hour post dose time point.
Time frame: Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose
Population: Pharmacokinetic (PK) data set included all participants who received at least 1 dose of daclatasvir with adequate PK profiles. The PK analysis was based on C-G CLcr grouping method: normal renal function (n=11), ESRD (n=10), moderate (n=5) and severe renal impairment (n=6). Mild participants (n=4) are also counted as per their original allocation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Unbound Apparent Clearance (CLU/F) of Daclatasvir | 11926.796 mL/min | Geometric Coefficient of Variation 53 |
| Mild Renal Impairment | Unbound Apparent Clearance (CLU/F) of Daclatasvir | 7802.955 mL/min | Geometric Coefficient of Variation 33 |
| Moderate Renal Impairment | Unbound Apparent Clearance (CLU/F) of Daclatasvir | 6900.602 mL/min | Geometric Coefficient of Variation 13 |
| Severe Renal Impairment | Unbound Apparent Clearance (CLU/F) of Daclatasvir | 7164.575 mL/min | Geometric Coefficient of Variation 41 |
| End Stage Renal Disease | Unbound Apparent Clearance (CLU/F) of Daclatasvir | 9926.962 mL/min | Geometric Coefficient of Variation 35 |
Secondary
Unbound Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity Time (AUC(INF)u) of Daclatasvir
AUC(INF)u was calculated by multiplying the area under the plasma concentration-time curve from time zero extrapolated to infinite time by mean fraction of unbound drug from 1 hour post-dose time point.
Time frame: Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose
Population: Pharmacokinetic (PK) data set included all participants who received at least 1 dose of daclatasvir with adequate PK profiles. The PK analysis was based on C-G CLcr grouping method: normal renal function (n=11), ESRD (n=10), moderate (n=5) and severe renal impairment (n=6). Mild participants (n=4) are also counted as per their original allocation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Unbound Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity Time (AUC(INF)u) of Daclatasvir | 83.845 ng*h/mL | Geometric Coefficient of Variation 37 |
| Mild Renal Impairment | Unbound Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity Time (AUC(INF)u) of Daclatasvir | 128.157 ng*h/mL | Geometric Coefficient of Variation 41 |
| Moderate Renal Impairment | Unbound Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity Time (AUC(INF)u) of Daclatasvir | 144.915 ng*h/mL | Geometric Coefficient of Variation 13 |
| Severe Renal Impairment | Unbound Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity Time (AUC(INF)u) of Daclatasvir | 139.576 ng*h/mL | Geometric Coefficient of Variation 43 |
| End Stage Renal Disease | Unbound Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity Time (AUC(INF)u) of Daclatasvir | 100.736 ng*h/mL | Geometric Coefficient of Variation 31 |
Secondary
Unbound Maximum Observed Plasma Concentrations of Daclatasvir
Unbound Maximum observed plasma concentrations (Cmaxu) was calculated by multiplying maximum observed plasma concentrations by mean fraction of unbound drug from 1 hour post-dose time point.
Time frame: Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose
Population: Pharmacokinetic (PK) data set included all participants who received at least 1 dose of daclatasvir with adequate PK profiles. The PK analysis was based on C-G CLcr grouping method: normal renal function (n=11), ESRD (n=10), moderate (n=5) and severe renal impairment (n=6). Mild participants (n=4) are also counted as per their original allocation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Unbound Maximum Observed Plasma Concentrations of Daclatasvir | 8.309 ng/mL | Geometric Coefficient of Variation 34 |
| Mild Renal Impairment | Unbound Maximum Observed Plasma Concentrations of Daclatasvir | 9.762 ng/mL | Geometric Coefficient of Variation 14 |
| Moderate Renal Impairment | Unbound Maximum Observed Plasma Concentrations of Daclatasvir | 10.206 ng/mL | Geometric Coefficient of Variation 20 |
| Severe Renal Impairment | Unbound Maximum Observed Plasma Concentrations of Daclatasvir | 7.677 ng/mL | Geometric Coefficient of Variation 33 |
| End Stage Renal Disease | Unbound Maximum Observed Plasma Concentrations of Daclatasvir | 7.668 ng/mL | Geometric Coefficient of Variation 36 |