Pharmacokinetic and Safety Study of Daclatasvir in Patients With Renal Impairment

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

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

Study Overview

• Status: Completed
• Conditions: Hepatitis C
• Intervention / Treatment: Drug: Daclatasvir

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Orlando, Florida, United States, 32809
      • Orlando Clinical Research Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • DaVita Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

- Meet renal function criteria in one of four categories

Exclusion Criteria:

- Unstable or uncontrolled medical conditions

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A (Normal renal function): Daclatasvir; Daclatasvir 60 mg tablet by mouth single dose on Day 1	Drug: Daclatasvir; Other Names: BMS-790052
Experimental: Group B (End Stage Renal Disease): Daclatasvir; Daclatasvir 60 mg tablet by mouth single dose on Day 1	Drug: Daclatasvir; Other Names: BMS-790052
Experimental: Group C (Moderate renal impairment): Daclatasvir; Daclatasvir 60 mg tablet by mouth single dose on Day 1	Drug: Daclatasvir; Other Names: BMS-790052
Experimental: Group D (Severe renal impairment): Daclatasvir; Daclatasvir 60 mg tablet by mouth single dose on Day 1	Drug: Daclatasvir; Other Names: BMS-790052

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Garimella T, Wang R, Luo WL, Hwang C, Sherman D, Kandoussi H, Marbury TC, Alcorn H, Bertz R, Bifano M. Single-dose pharmacokinetics and safety of daclatasvir in subjects with renal function impairment. Antivir Ther. 2015;20(5):535-43. doi: 10.3851/IMP2941. Epub 2015 Feb 5.

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): June 1, 2013
• Study Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: April 10, 2013
• First Submitted That Met QC Criteria: April 10, 2013
• First Posted (Estimate): April 12, 2013

Study Record Updates

• Last Update Posted (Estimate): November 16, 2015
• Last Update Submitted That Met QC Criteria: November 13, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Hepatitis; Hepatitis C
• Other Study ID Numbers: AI444-063