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Pharmacokinetics and Pharmacodynamics of Apixaban in Subjects on Hemodialysis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT01340586
First received: April 21, 2011
Last updated: August 17, 2016
Last verified: August 2016
  Purpose
The purpose of this study is to assess the pharmacokinetics of a single oral dose of 5 mg Apixaban in subjects with normal renal function and subjects with end stage renal disease (ESRD) maintained with hemodialysis.

Condition Intervention Phase
End Stage Renal Disease
Drug: Apixaban
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Official Title: Single-Dose Study to Evaluate the Pharmacokinetics, Pharmacodynamics, and Safety of Apixaban in Subjects on Hemodialysis

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Single 5mg Oral Dose of Apixaban [ Time Frame: 24 hours pre-dose to 72 hours post-dose ] [ Designated as safety issue: No ]
    Maximum observed plasma concentration (Cmax) was measured by plasma concentration of apixaban over time. The geometric means are reported in nanograms per milliliter (ng/mL).

  • Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Metabolite BMS-730823 [ Time Frame: From 24 hours pre-dose to 72 hours post-dose ] [ Designated as safety issue: No ]
    Maximum observed plasma concentration (Cmax) was measured by plasma concentration of BMS-730823 over time. The geometric means are reported in nanograms per milliliter (ng/mL).

  • Geometric Mean of Area Under the Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC(0-T)) of Single 5mg Oral Dose of Apixaban [ Time Frame: 24 hours pre-dose to 72 hours post-dose ] [ Designated as safety issue: No ]
    Area under the concentration-time curve from time zero to time of the last quantifiable concentration (AUC(0-T)) was measured by plasma concentration of apixaban over time. The geometric means are reported in nanogram hours per milliliter (ng*h/mL).

  • Geometric Mean of Area Under the Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC(0-T)) of Metabolite BMS-730823 [ Time Frame: From 24 hours pre-dose to 72 hours post-dose ] [ Designated as safety issue: No ]
    Area under the concentration-time curve from time zero to time of the last quantifiable concentration (AUC(0-T)) was measured by plasma concentration of BMS-730823 over time. The geometric means are reported in nanogram hours per milliliter (ng*h/mL).

  • Geometric Mean of Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinite Time (AUC(INF)) of Single 5mg Oral Dose of Apixaban [ Time Frame: From 24 hours pre-dose to 72 hours post-dose ] [ Designated as safety issue: No ]
    The area under the concentration-time curve from time zero extrapolated to infinite time (AUC(INF)) was measured by plasma concentration of apixaban over time. The geometric means are reported in nanogram hours per milliliter (ng*h/mL).

  • Geometric Mean of Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinite Time (AUC(INF)) of BMS-730823 [ Time Frame: 24 hours pre-dose to 72 hours post-dose ] [ Designated as safety issue: No ]
    The area under the concentration-time curve from time zero extrapolated to infinite time (AUC(INF)) was measured by plasma concentration of BMS-730823 over time. The geometric means are reported in nanogram hours per milliliter (ng*h/mL).

  • Mean Plasma Terminal Half-life (T-Half) of Single 5mg Oral Dose of Apixaban [ Time Frame: From 24 hours pre-dose to 72 hours post-dose ] [ Designated as safety issue: No ]
    Plasma terminal half-life (T-Half) for apixaban was derived from plasma concentrations versus time data. Means were reported in hours.

  • Mean Plasma Terminal Half-life (T-Half) of BMS-730823 [ Time Frame: 24 hours pre-dose to 72 hours post-dose ] [ Designated as safety issue: No ]
    Mean plasma terminal half-life (T-Half) for BMS-730823 was derived from plasma concentrations versus time data.

  • Median Time of Maximum Observed Plasma Concentration (Tmax) of a Single 5 mg Oral Dose of Apixaban [ Time Frame: From 24 hours pre-dose to 72 hours post-dose ] [ Designated as safety issue: No ]
    Time of maximum observed plasma concentration (Tmax) for apixaban was derived from plasma concentrations versus time data. Medians were reported in hours.

  • Median Time of Maximum Observed Plasma Concentration (Tmax) of Metabolite BMS-730823 [ Time Frame: From 24 hours pre-dose to 72 hours post-dose ] [ Designated as safety issue: No ]
    Time of maximum observed plasma concentration (Tmax) for BMS-730823 was derived from plasma concentrations versus time data. Medians were reported in hours.

  • Geometric Mean of Area Under the Plasma Concentration-Time Curve From 2 to 6 Hours (AUC(2-6)) for Apixaban [ Time Frame: 2 to 6 hours post-dose ] [ Designated as safety issue: No ]
    Area under the plasma concentration-time curve from 2 hours to 6 hours (AUC(2-6) for Apixaban was measured in participants with ESRD during dialysis in Period 1 only. Geometric Means were reported in nanogram hours per milliliter (ng*hr/mL) and were determined from blood samples both entering and exiting the dialyzer.

  • Geometric Mean of Area Under the Plasma Concentration-Time Curve From 2 to 6 Hours (AUC(2-6)) for BMS-730823 [ Time Frame: 2 to 6 hours post-dose ] [ Designated as safety issue: No ]
    Area under the plasma concentration-time curve from 2 hours to 6 hours (AUC(2-6) for BMS-730823 was measured in participants with ESRD during dialysis in Period 1 only. Geometric Means were reported in nanogram hours per milliliter (ng*hr/mL) and were determined from blood samples both entering and exiting the dialyzer.

  • Mean Percent Dose of Apixaban Recovered in Urine (%UR) [ Time Frame: 24 hours pre-dose to 72 hours post-dose ] [ Designated as safety issue: No ]
    The percent dose recovered in urine was calculated by dividing the cumulative amount of unchanged apixaban excreted in urine from the time of dose up to 72 hours post-dose by the apixaban dose administered.

  • Mean Percent Dose of Apixaban Recovered in Dialysate (%DR) [ Time Frame: 2 to 6 hours post-dose ] [ Designated as safety issue: No ]
    Percent dose of Apixaban recovered in dialysate (%DR) was calculated by dividing the cumulative amount of apixaban excreted in each dialysate collection over 2-6 hours (DR(2-6)) by the apixaban dose. %DR was recorded only in period 1.

  • Mean Renal Clearance (CLR) of Apixaban [ Time Frame: 24 hours pre-dose to 72 hours post-dose ] [ Designated as safety issue: No ]
    Renal clearance (CLR) was calculated by dividing the cumulative amount of apixaban excreted in urine by the respective cumulative plasma AUC over the same urine collection interval. Geometric means were reported in milliliters per minute (mL/min).

  • Mean Renal Clearance (CLR) of BMS-730823 [ Time Frame: 24 hours pre-dose to 72 hours post-dose ] [ Designated as safety issue: No ]
    Renal clearance (CLR) was calculated by dividing the cumulative amount of BMS-730823 excreted in urine by the respective cumulative plasma AUC over the same urine collection interval. Geometric means were reported in milliliters per minute (mL/min).

  • Mean Hemodialysis Clearance (CLD) of Apixaban [ Time Frame: 2 to 6 hours post-dose ] [ Designated as safety issue: No ]
    Hemodialysis clearance (CLD) was calculated by dividing the cumulative amount of apixaban excreted in dialysate by the respective cumulative plasma AUC over the same dialysate collection interval (AUC(2-6) entering). CLD measurements occurred only in period 1. Geometric means were reported in milliliters per minute (mL/min).

  • Mean Hemodialysis Clearance (CLD) of BMS-730823 [ Time Frame: 2 to 6 hours post-dose ] [ Designated as safety issue: No ]
    Hemodialysis clearance (CLD) was calculated by dividing the cumulative amount of BMS-730823 excreted in dialysate by the respective cumulative plasma AUC over the same dialysate collection interval (AUC(2-6) entering). CLD measurements occurred only in period 1. Geometric means were reported in milliliters per minute (mL/min).

  • Percentage of Apixaban Extracted During Hemodialysis [ Time Frame: 2 to 6 hours post-dose ] [ Designated as safety issue: No ]
    The percentage of apixaban extracted during hemodialysis (extraction ratio) was calculated using the formula [plasma AUC(2-6) exiting - AUC(2-6) entering] / [AUC(2-6) entering] and converted to a percentage. The extraction ratio was measured in period 1 only, and was reported as a percentage.

  • Percentage of BMS-730823 Extracted During Hemodialysis [ Time Frame: 2 to 6 hours post-dose ] [ Designated as safety issue: No ]
    The percentage of BMS-730823 extracted during hemodialysis (extraction ratio) was calculated using the formula [plasma AUC(2-6)exiting - AUC(2-6)entering] / [AUC(2-6) entering] and converted to a percentage. The extraction ratio was measured in period 1 only, and was reported as a percentage.


Secondary Outcome Measures:
  • Mean Maximum Percent Change From Baseline International Normalized Ratio (INR) Following a Single 5 mg Oral Dose of Apixaban [ Time Frame: From 24 hours pre-dose to 72 hours post-dose ] [ Designated as safety issue: No ]
    The mean maximum percent change in baseline for INR was reported for each arm. Baseline measurements were assessed up to 24 hours prior to Day 1 dosing.

  • Mean Maximum Percent Change From Baseline Prothrombin Time (PT) Following a Single 5 mg Oral Dose of Apixaban [ Time Frame: From 24 hours pre-dose to 72 hours post-dose ] [ Designated as safety issue: No ]
    The mean maximum percent change in Prothrombin Time (PT) from baseline was reported for all treated participants. Baseline measurements were assessed up to 24 hours prior to Day 1 dosing.

  • Mean Maximum Percent Change From Baseline Activated Partial Thromboplastin Time (aPTT) Following a Single Oral Dose of 5 mg Apixaban [ Time Frame: From 24 hours pre-dose to 72 hours post-dose ] [ Designated as safety issue: No ]
    The mean maximum percent change in Activated Partial Thromboplastin Time (aPTT) from baseline was reported for all treated participants. Baseline measurements were assessed up to 24 hours prior to Day 1 dosing.

  • Mean Peak Anti-FXa Activity Following a Single Oral Dose of 5 mg Apixaban [ Time Frame: From 24 hours pre-dose to 72 hours post-dose ] [ Designated as safety issue: No ]
    Anti-FXa activity was assessed from an activity-time profile for doses both before and after hemodialysis. Maximal means were reported in International Units per milliliter (IU/mL).


Other Outcome Measures:
  • Number of Participants With Laboratory Marked Abnormalities [ Time Frame: From 24 hours pre-dose to 72 hours post-dose ] [ Designated as safety issue: Yes ]

    ULN=Upper Limit of Normal, LLN=Lower Limit of Normal, Pre-Rx= Baseline value. BUN=Blood Urea Nitrogen (mmol/L=millimoles per Liter): High if BUN > 1.1*ULN (if Pre-Rx>ULN: >1.25*Pre-Rx).

    Platelet count (*10^9 cell/L): Low if Platelet Count < 0.85*LLN (if Pre-Rx<LLN: <0.85*Pre-Rx).

    Creatine (umol/L=micromoles per Liter): High if Creatine > 1.5*ULN (if Pre-Rx>ULN: >1.33*Pre-Rx).

    Calcium, Total (mmol/L): High if Calcium > 1.5*ULN (if Pre-Rx>ULN: >1.33*Pre-Rx).

    Potassium, serum (mmol/L): High if Potassium > 1.1*ULN (if Pre-Rx>ULN: >1.1*Pre-Rx; if Pre-Rx<LLN: >ULN).

    Phosphorus, Inorganic (mmol/L): Low if Phosphate < 0.85*LLN (if Pre-Rx>ULN: <LLN).

    Lactate dehydrogenase (U/L=Units per Liter): High if Lactate Dehydrogenase > 1.25*ULN (if Pre-Rx>ULN: >1.5*Pre-Rx).


  • Number of Participants Who Died or Experienced Serious Adverse Events (SAEs) or Adverse Events Leading to Discontinuation [ Time Frame: From Day 1 to 30 days post study discontinuation ] [ Designated as safety issue: Yes ]

    The number of participants who died or experienced SAEs or AEs leading to discontinuation was reported for each arm.

    AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling.



Enrollment: 18
Study Start Date: June 2011
Study Completion Date: September 2011
Primary Completion Date: September 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group A: Apixaban Drug: Apixaban
Tablets, Oral, 5 mg, Once, 4 days
Experimental: Group B: Apixaban Drug: Apixaban
Tablets, Oral, 5 mg, Twice, 15 days

Detailed Description:
Primary Purpose : To provide a clear understanding of the pharmacokinetics of Apixaban in subjects with ESRD and to determine the effect of hemodialysis on Apixaban pharmacokinetics .
  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • The signed informed consent form.
  • Subjects with normal renal function classified based on calculated creatinine clearance (CLCr) determined by the cockcroft-gault calculation.
  • Eligible subjects with ESRD that is maintained with chronic and stable hemodialysis.

Exclusion Criteria:

  • Any history of abnormal bleeding or coagulation disorders including those in a first degree relative under 50 years of age.
  • History of significant head injury within the last two years.
  • Any gastrointestinal surgery that could impact the absorption of study drug.
  • Not expected to continue the hemodialysis treatment for the duration of the study.
  • INR, PT, or aPTT above the upper limit of normal, unless agreed upon between the investigator and BMS medical monitor.
  • History of allergy to Apixaban or Factor Xa inhibitors.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01340586

Locations
United States, Florida
Orlando, Florida, United States
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
Publications:
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT01340586     History of Changes
Other Study ID Numbers: CV185-087 
Study First Received: April 21, 2011
Results First Received: March 29, 2016
Last Updated: August 17, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Bristol-Myers Squibb:
PHARMACOKINETIC
NOS

Additional relevant MeSH terms:
Kidney Failure, Chronic
Renal Insufficiency, Chronic
Renal Insufficiency
Kidney Diseases
Urologic Diseases
Apixaban
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants

ClinicalTrials.gov processed this record on December 09, 2016