Pharmacokinetics and Pharmacodynamics of Apixaban in Subjects on Hemodialysis

Phase 1

Completed

• Conditions: End Stage Renal Disease
• Interventions: Drug: Apixaban

• Registration Number: NCT01340586
• Lead Sponsor: Bristol-Myers Squibb

Brief Summary

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

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 Timeline

• Study First Submitted: 2011-04-21
• Study First Submitted QC: 2011-04-21
• Study First Posted: 2011-04-22
• Study Start: 2011-06
• Primary Completion: 2011-09
• Study Completion: 2011-09
• Results First Submitted: 2016-03-29
• Status Verified: 2016-08
• Results First Submitted QC: 2016-08-17
• Last Update Submitted: 2016-08-17
• Results First Posted: 2016-10-11
• Last Update Posted: 2016-10-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 18

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group A: Apixaban	Apixaban	-
Group B: Apixaban	Apixaban	-

Primary Outcome Measures

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

Secondary Outcome Measures

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