Pharmacokinetics and Pharmacodynamics of Apixaban in Subjects on Hemodialysis

Study Overview
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Brief Summary
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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.

Detailed Description
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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 .

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

Conditions
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End Stage Renal Disease

Intervention / Treatment
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* Drug: Apixaban
* Drug: Apixaban


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: Apixaban<br> | Drug: Apixaban<br>* Tablets, Oral, 5 mg, Once, 4 days<br>|
| Experimental: Group B: Apixaban<br> | Drug: Apixaban<br>* Tablets, Oral, 5 mg, Twice, 15 days<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PHARMACOKINETIC, NOS