Pharmacokinetic and Safety Study of Daclatasvir in Patients With Renal Impairment

Study Overview
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Brief Summary
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The purpose of this study is to assess the effect of renal function impairment on the single dose pharmacokinetics of Daclatasvir.

Detailed Description
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Treatment, Parallel Assignment, Open Label, Non-Randomized, Single Dose Adaptive Design, Pharmacokinetics Study

Official Title
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Single Dose Pharmacokinetics and Safety of Daclatasvir in Subjects With Renal Function Impairment

Conditions
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Hepatitis C

Intervention / Treatment
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* Drug: Daclatasvir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Meet renal function criteria in one of four categories Exclusion Criteria: - Unstable or uncontrolled medical conditions

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Group A (Normal renal function): Daclatasvir<br>Daclatasvir 60 mg tablet by mouth single dose on Day 1 | Drug: Daclatasvir<br> <br> * Other names: BMS-790052;|
| Experimental: Group B (End Stage Renal Disease): Daclatasvir<br>Daclatasvir 60 mg tablet by mouth single dose on Day 1 | Drug: Daclatasvir<br> <br> * Other names: BMS-790052;|
| Experimental: Group C (Moderate renal impairment): Daclatasvir<br>Daclatasvir 60 mg tablet by mouth single dose on Day 1 | Drug: Daclatasvir<br> <br> * Other names: BMS-790052;|
| Experimental: Group D (Severe renal impairment): Daclatasvir<br>Daclatasvir 60 mg tablet by mouth single dose on Day 1 | Drug: Daclatasvir<br> <br> * Other names: BMS-790052;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 (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. | 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 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. | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | 
| 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. | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | 
| 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. | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | 
| 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. | 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 (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. | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | 
| 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. | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | 
| 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. | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | 
| 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. | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | 
| 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. | Pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose | 
| 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. | First dose up to Day 5 post last dose for AEs; up to 30 days post last dose for SAEs | 
| 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. | Baseline up to Day 5 post dose | 
| 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. | Baseline up to Day 5 post dose | 
| 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. | Baseline up to Day 5 post dose |