Pharmacokinetics and Pharmacodynamics of Apixaban in Subjects on Hemodialysis

Single-Dose Study to Evaluate the Pharmacokinetics, Pharmacodynamics, and Safety of Apixaban in Subjects on Hemodialysis

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.

Study Overview

• Status: Completed
• Conditions: End Stage Renal Disease
• Intervention / Treatment: Drug: Apixaban; Drug: Apixaban

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 .

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Orlando, Florida, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A: Apixaban	Drug: Apixaban; Tablets, Oral, 5 mg, Once, 4 days; Drug: Apixaban; Tablets, Oral, 5 mg, Twice, 15 days
Experimental: Group B: Apixaban	Drug: Apixaban; Tablets, Oral, 5 mg, Once, 4 days; Drug: Apixaban; Tablets, Oral, 5 mg, Twice, 15 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Single 5mg Oral Dose of Apixaban	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).	24 hours pre-dose to 72 hours post-dose
Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Metabolite BMS-730823	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).	From 24 hours pre-dose to 72 hours post-dose
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	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).	24 hours pre-dose to 72 hours post-dose
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	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).	From 24 hours pre-dose to 72 hours post-dose
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	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).	From 24 hours pre-dose to 72 hours post-dose
Geometric Mean of Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinite Time (AUC(INF)) of BMS-730823	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).	24 hours pre-dose to 72 hours post-dose
Mean Plasma Terminal Half-life (T-Half) of Single 5mg Oral Dose of Apixaban	Plasma terminal half-life (T-Half) for apixaban was derived from plasma concentrations versus time data. Means were reported in hours.	From 24 hours pre-dose to 72 hours post-dose
Mean Plasma Terminal Half-life (T-Half) of BMS-730823	Mean plasma terminal half-life (T-Half) for BMS-730823 was derived from plasma concentrations versus time data.	24 hours pre-dose to 72 hours post-dose
Median Time of Maximum Observed Plasma Concentration (Tmax) of a Single 5 mg Oral Dose of Apixaban	Time of maximum observed plasma concentration (Tmax) for apixaban was derived from plasma concentrations versus time data. Medians were reported in hours.	From 24 hours pre-dose to 72 hours post-dose
Median Time of Maximum Observed Plasma Concentration (Tmax) of Metabolite BMS-730823	Time of maximum observed plasma concentration (Tmax) for BMS-730823 was derived from plasma concentrations versus time data. Medians were reported in hours.	From 24 hours pre-dose to 72 hours post-dose
Geometric Mean of Area Under the Plasma Concentration-Time Curve From 2 to 6 Hours (AUC(2-6)) for Apixaban	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.	2 to 6 hours post-dose
Geometric Mean of Area Under the Plasma Concentration-Time Curve From 2 to 6 Hours (AUC(2-6)) for BMS-730823	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.	2 to 6 hours post-dose
Mean Percent Dose of Apixaban Recovered in Urine (%UR)	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.	24 hours pre-dose to 72 hours post-dose
Mean Percent Dose of Apixaban Recovered in Dialysate (%DR)	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.	2 to 6 hours post-dose
Mean Renal Clearance (CLR) of Apixaban	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).	24 hours pre-dose to 72 hours post-dose
Mean Renal Clearance (CLR) of BMS-730823	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).	24 hours pre-dose to 72 hours post-dose
Mean Hemodialysis Clearance (CLD) of Apixaban	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).	2 to 6 hours post-dose
Mean Hemodialysis Clearance (CLD) of BMS-730823	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).	2 to 6 hours post-dose
Percentage of Apixaban Extracted During Hemodialysis	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.	2 to 6 hours post-dose
Percentage of BMS-730823 Extracted During Hemodialysis	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.	2 to 6 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Maximum Percent Change From Baseline International Normalized Ratio (INR) Following a Single 5 mg Oral Dose of Apixaban	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.	From 24 hours pre-dose to 72 hours post-dose
Mean Maximum Percent Change From Baseline Prothrombin Time (PT) Following a Single 5 mg Oral Dose of Apixaban	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.	From 24 hours pre-dose to 72 hours post-dose
Mean Maximum Percent Change From Baseline Activated Partial Thromboplastin Time (aPTT) Following a Single Oral Dose of 5 mg Apixaban	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.	From 24 hours pre-dose to 72 hours post-dose
Mean Peak Anti-FXa Activity Following a Single Oral Dose of 5 mg Apixaban	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).	From 24 hours pre-dose to 72 hours post-dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Laboratory Marked Abnormalities	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).	From 24 hours pre-dose to 72 hours post-dose
Number of Participants Who Died or Experienced Serious Adverse Events (SAEs) or Adverse Events Leading to Discontinuation	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.	From Day 1 to 30 days post study discontinuation

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Wang X, Tirucherai G, Marbury TC, Wang J, Chang M, Zhang D, Song Y, Pursley J, Boyd RA, Frost C. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol. 2016 May;56(5):628-36. doi: 10.1002/jcph.628. Epub 2015 Dec 22.

Helpful Links

• BMS clinical trial educational resource

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): September 1, 2011
• Study Completion (Actual): September 1, 2011

Study Registration Dates

• First Submitted: April 21, 2011
• First Submitted That Met QC Criteria: April 21, 2011
• First Posted (Estimate): April 22, 2011

Study Record Updates

• Last Update Posted (Estimate): October 11, 2016
• Last Update Submitted That Met QC Criteria: August 17, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: NOS; PHARMACOKINETIC
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Apixaban
• Other Study ID Numbers: CV185-087