End Stage Renal Disease
Conditions
Keywords
PHARMACOKINETIC, NOS
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 .
Interventions
DRUGApixaban
Tablets, Oral, 5 mg, Once, 4 days
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 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). |
| 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). |
| 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). |
| 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 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. |
| 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). |
| 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 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). |
| 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 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 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. |
| 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. |
| 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. |
| 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. |
| 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 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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 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). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Died or Experienced Serious Adverse Events (SAEs) or Adverse Events Leading to Discontinuation | From Day 1 to 30 days post study 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. |
| Number of Participants With Laboratory Marked Abnormalities | From 24 hours pre-dose to 72 hours post-dose | 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). |
Countries
United States
Participant flow
Pre-assignment details
A total of 18 participants were enrolled in this study. 16 participants were treated and completed the study. Two participants were enrolled but not treated (one withdrew consent, one enrolled as alternate).
Participants by arm
| Arm | Count |
|---|---|
| Normal Renal Function Healthy participants with normal renal function (calculated creatinine clearance (ClCr) \> 80 mL/min) received a single oral dose of 5 mg apixaban on the morning of Day 1. | 8 |
| ESRD Maintained With Hemodialysis Participants with End Stage Renal Disease (ESRD) maintained with hemodialysis received two doses of apixaban separated by a washout period of at least 7 days; one oral dose of 5mg apixaban 2 hours prior to hemodialysis on Day 1 of Period 1, and a second oral dose of 5mg apixaban immediately following the hemodialysis session on Day 1, Period 2. | 8 |
| Total | 16 |
Baseline characteristics
| Characteristic | Normal Renal Function | ESRD Maintained With Hemodialysis | Total |
|---|---|---|---|
| Age, Continuous | 47.0 years STANDARD_DEVIATION 7.7 | 46.9 years STANDARD_DEVIATION 7.9 | 46.9 years STANDARD_DEVIATION 7.5 |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 8 | 2 / 8 | 1 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
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).
Time frame: 24 hours pre-dose to 72 hours post-dose
Population: All treated participants
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Normal Renal Function | Geometric Mean of Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinite Time (AUC(INF)) of BMS-730823 | NA ng*h/mL |
| ESRD Dose Before Hemodialysis | Geometric Mean of Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinite Time (AUC(INF)) of BMS-730823 | NA ng*h/mL |
| ESRD Dose After Hemodialysis | Geometric Mean of Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinite Time (AUC(INF)) of BMS-730823 | NA ng*h/mL |
Primary
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).
Time frame: From 24 hours pre-dose to 72 hours post-dose
Population: All treated participants
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | 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 | 1265 ng*hr/mL | Geometric Coefficient of Variation 30 |
| ESRD Dose Before Hemodialysis | 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 | 1474 ng*hr/mL | Geometric Coefficient of Variation 44 |
| ESRD Dose After Hemodialysis | 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 | 1717 ng*hr/mL | Geometric Coefficient of Variation 24 |
Comparison: Geometric Mean Ratio: ESRD Dose before hemodialysis over Normal Renal Function90% CI: [0.88, 1.543]
Comparison: Geometric Mean Ratio: ESRD Dose after hemodialysis over Normal Renal Function90% CI: [1.066, 1.728]
Comparison: Geometric Mean Ratio: ESRD Dose before hemodialysis over ESRD Dose after hemodialysis90% CI: [0.707, 1.042]
Primary
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).
Time frame: From 24 hours pre-dose to 72 hours post-dose
Population: All treated participants
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | 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 | 205 ng*hr/mL | Geometric Coefficient of Variation 69 |
| ESRD Dose Before Hemodialysis | 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 | 746 ng*hr/mL | Geometric Coefficient of Variation 56 |
| ESRD Dose After Hemodialysis | 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 | 953 ng*hr/mL | Geometric Coefficient of Variation 33 |
Primary
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).
Time frame: 24 hours pre-dose to 72 hours post-dose
Population: All treated participants
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | 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 | 1205 ng*hr/mL | Geometric Coefficient of Variation 29 |
| ESRD Dose Before Hemodialysis | 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 | 1430 ng*hr/mL | Geometric Coefficient of Variation 41 |
| ESRD Dose After Hemodialysis | 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 | 1673 ng*hr/mL | Geometric Coefficient of Variation 24 |
Comparison: Geometric Mean Ratio: ESRD Dose before hemodialysis over Normal Renal Function90% CI: [0.907, 1.553]
Comparison: Geometric Mean Ratio: ESRD Dose after hemodialysis over Normal Renal Function90% CI: [1.097, 1.758]
Comparison: Geometric Mean Ratio: ESRD Dose before hemodialysis over ESRD Dose after hemodialysis90% CI: [0.707, 1.033]
Primary
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.
Time frame: 2 to 6 hours post-dose
Population: All participants with ESRD maintained with hemodialysis
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Renal Function | Geometric Mean of Area Under the Plasma Concentration-Time Curve From 2 to 6 Hours (AUC(2-6)) for Apixaban | Blood entering dialyzer | 309 ng*hr/mL | Geometric Coefficient of Variation 29 |
| Normal Renal Function | Geometric Mean of Area Under the Plasma Concentration-Time Curve From 2 to 6 Hours (AUC(2-6)) for Apixaban | Blood exiting dialyzer | 312 ng*hr/mL | Geometric Coefficient of Variation 28 |
Primary
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.
Time frame: 2 to 6 hours post-dose
Population: All participants with ESRD maintained with hemodialysis
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Renal Function | Geometric Mean of Area Under the Plasma Concentration-Time Curve From 2 to 6 Hours (AUC(2-6)) for BMS-730823 | Blood entering dialyzer | 15.0 ng*hr/mL | Geometric Coefficient of Variation 102 |
| Normal Renal Function | Geometric Mean of Area Under the Plasma Concentration-Time Curve From 2 to 6 Hours (AUC(2-6)) for BMS-730823 | Blood exiting dialyzer | 17.7 ng*hr/mL | Geometric Coefficient of Variation 96 |
Primary
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).
Time frame: From 24 hours pre-dose to 72 hours post-dose
Population: All treated participants
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Metabolite BMS-730823 | 10.8 ng/mL | Geometric Coefficient of Variation 38 |
| ESRD Dose Before Hemodialysis | Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Metabolite BMS-730823 | 15.9 ng/mL | Geometric Coefficient of Variation 48 |
| ESRD Dose After Hemodialysis | Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Metabolite BMS-730823 | 20.0 ng/mL | Geometric Coefficient of Variation 39 |
Primary
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).
Time frame: 24 hours pre-dose to 72 hours post-dose
Population: All treated participants
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Single 5mg Oral Dose of Apixaban | 125.6 ng/mL | Geometric Coefficient of Variation 29 |
| ESRD Dose Before Hemodialysis | Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Single 5mg Oral Dose of Apixaban | 98.9 ng/mL | Geometric Coefficient of Variation 29 |
| ESRD Dose After Hemodialysis | Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Single 5mg Oral Dose of Apixaban | 113.6 ng/mL | Geometric Coefficient of Variation 31 |
Comparison: Geometric Mean Ratio: ESRD Dose before hemodialysis over Normal Renal Function90% CI: [0.616, 1.006]
Comparison: Geometric Mean Ratio: ESRD Dose after hemodialysis over Normal Renal Function90% CI: [0.697, 1.173]
Comparison: Geometric Mean Ratio: ESRD Dose before hemodialysis over ESRD Dose after hemodialysis90% CI: [0.723, 1.049]
Primary
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).
Time frame: 2 to 6 hours post-dose
Population: All treated participants with ESRD maintained with hemodialysis
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Mean Hemodialysis Clearance (CLD) of Apixaban | 17.7 mL/min | Geometric Coefficient of Variation 19 |
Primary
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).
Time frame: 2 to 6 hours post-dose
Population: All participants with ESRD maintained with hemodialysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Normal Renal Function | Mean Hemodialysis Clearance (CLD) of BMS-730823 | NA mL/min |
Primary
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.
Time frame: 2 to 6 hours post-dose
Population: All treated participants with ESRD maintained with hemodialysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Mean Percent Dose of Apixaban Recovered in Dialysate (%DR) | 6.68 percent of dose recovered in dialysate | Standard Deviation 1.408 |
Primary
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.
Time frame: 24 hours pre-dose to 72 hours post-dose
Population: All treated participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Mean Percent Dose of Apixaban Recovered in Urine (%UR) | 18.397 percent of dose recovered in urine | Standard Deviation 8.5545 |
| ESRD Dose Before Hemodialysis | Mean Percent Dose of Apixaban Recovered in Urine (%UR) | 0.145 percent of dose recovered in urine | Standard Deviation 0.0881 |
| ESRD Dose After Hemodialysis | Mean Percent Dose of Apixaban Recovered in Urine (%UR) | 0.181 percent of dose recovered in urine | Standard Deviation 0.1391 |
Primary
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.
Time frame: 24 hours pre-dose to 72 hours post-dose
Population: All treated participants with ESRD maintained with hemodialysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Normal Renal Function | Mean Plasma Terminal Half-life (T-Half) of BMS-730823 | NA hours |
Primary
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.
Time frame: From 24 hours pre-dose to 72 hours post-dose
Population: All treated participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Mean Plasma Terminal Half-life (T-Half) of Single 5mg Oral Dose of Apixaban | 20.0 hours | Standard Deviation 14.45 |
| ESRD Dose Before Hemodialysis | Mean Plasma Terminal Half-life (T-Half) of Single 5mg Oral Dose of Apixaban | 12.5 hours | Standard Deviation 3.14 |
| ESRD Dose After Hemodialysis | Mean Plasma Terminal Half-life (T-Half) of Single 5mg Oral Dose of Apixaban | 12.7 hours | Standard Deviation 3.4 |
Primary
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).
Time frame: 24 hours pre-dose to 72 hours post-dose
Population: All treated participants
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Mean Renal Clearance (CLR) of Apixaban | 11.263 mL/min | Geometric Coefficient of Variation 44 |
| ESRD Dose Before Hemodialysis | Mean Renal Clearance (CLR) of Apixaban | 0.020 mL/min | Geometric Coefficient of Variation 70 |
| ESRD Dose After Hemodialysis | Mean Renal Clearance (CLR) of Apixaban | 0.020 mL/min | Geometric Coefficient of Variation 80 |
Primary
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).
Time frame: 24 hours pre-dose to 72 hours post-dose
Population: All treated participants
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Mean Renal Clearance (CLR) of BMS-730823 | 6.36 mL/min | Geometric Coefficient of Variation 62 |
| ESRD Dose Before Hemodialysis | Mean Renal Clearance (CLR) of BMS-730823 | NA mL/min | — |
| ESRD Dose After Hemodialysis | Mean Renal Clearance (CLR) of BMS-730823 | NA mL/min | — |
Primary
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.
Time frame: From 24 hours pre-dose to 72 hours post-dose
Population: All treated participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normal Renal Function | Median Time of Maximum Observed Plasma Concentration (Tmax) of a Single 5 mg Oral Dose of Apixaban | 2.00 hours |
| ESRD Dose Before Hemodialysis | Median Time of Maximum Observed Plasma Concentration (Tmax) of a Single 5 mg Oral Dose of Apixaban | 2.00 hours |
| ESRD Dose After Hemodialysis | Median Time of Maximum Observed Plasma Concentration (Tmax) of a Single 5 mg Oral Dose of Apixaban | 2.00 hours |
Primary
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.
Time frame: From 24 hours pre-dose to 72 hours post-dose
Population: All treated participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normal Renal Function | Median Time of Maximum Observed Plasma Concentration (Tmax) of Metabolite BMS-730823 | 9.00 hours |
| ESRD Dose Before Hemodialysis | Median Time of Maximum Observed Plasma Concentration (Tmax) of Metabolite BMS-730823 | 15.00 hours |
| ESRD Dose After Hemodialysis | Median Time of Maximum Observed Plasma Concentration (Tmax) of Metabolite BMS-730823 | 21.00 hours |
Primary
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.
Time frame: 2 to 6 hours post-dose
Population: All treated participants with ESRD maintained with hemodialysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Percentage of Apixaban Extracted During Hemodialysis | -1.1 percentage of apixaban extracted | Standard Deviation 5.65 |
Primary
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.
Time frame: 2 to 6 hours post-dose
Population: All treated participants with ESRD maintained with hemodialysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Percentage of BMS-730823 Extracted During Hemodialysis | -19.9 percentage of BMS-730823 extracted | Standard Deviation 25.32 |
Secondary
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.
Time frame: From 24 hours pre-dose to 72 hours post-dose
Population: All treated participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Mean Maximum Percent Change From Baseline Activated Partial Thromboplastin Time (aPTT) Following a Single Oral Dose of 5 mg Apixaban | 19.9 maximum percent change from baseline | Standard Deviation 20.4 |
| ESRD Dose Before Hemodialysis | Mean Maximum Percent Change From Baseline Activated Partial Thromboplastin Time (aPTT) Following a Single Oral Dose of 5 mg Apixaban | 7.0 maximum percent change from baseline | Standard Deviation 9.62 |
| ESRD Dose After Hemodialysis | Mean Maximum Percent Change From Baseline Activated Partial Thromboplastin Time (aPTT) Following a Single Oral Dose of 5 mg Apixaban | 23.0 maximum percent change from baseline | Standard Deviation 14.81 |
Secondary
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.
Time frame: From 24 hours pre-dose to 72 hours post-dose
Population: All treated participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Mean Maximum Percent Change From Baseline International Normalized Ratio (INR) Following a Single 5 mg Oral Dose of Apixaban | 31.5 maximum percent change from baseline | Standard Deviation 56.59 |
| ESRD Dose Before Hemodialysis | Mean Maximum Percent Change From Baseline International Normalized Ratio (INR) Following a Single 5 mg Oral Dose of Apixaban | 16.6 maximum percent change from baseline | Standard Deviation 10.6 |
| ESRD Dose After Hemodialysis | Mean Maximum Percent Change From Baseline International Normalized Ratio (INR) Following a Single 5 mg Oral Dose of Apixaban | 16.8 maximum percent change from baseline | Standard Deviation 7.15 |
Secondary
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.
Time frame: From 24 hours pre-dose to 72 hours post-dose
Population: All treated participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Mean Maximum Percent Change From Baseline Prothrombin Time (PT) Following a Single 5 mg Oral Dose of Apixaban | 32.4 maximum percent change from baseline | Standard Deviation 58.31 |
| ESRD Dose Before Hemodialysis | Mean Maximum Percent Change From Baseline Prothrombin Time (PT) Following a Single 5 mg Oral Dose of Apixaban | 16.9 maximum percent change from baseline | Standard Deviation 10.98 |
| ESRD Dose After Hemodialysis | Mean Maximum Percent Change From Baseline Prothrombin Time (PT) Following a Single 5 mg Oral Dose of Apixaban | 17.4 maximum percent change from baseline | Standard Deviation 7.28 |
Secondary
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).
Time frame: From 24 hours pre-dose to 72 hours post-dose
Population: All treated participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Mean Peak Anti-FXa Activity Following a Single Oral Dose of 5 mg Apixaban | 1.47 IU/mL | Standard Deviation 0.659 |
| ESRD Dose Before Hemodialysis | Mean Peak Anti-FXa Activity Following a Single Oral Dose of 5 mg Apixaban | 1.03 IU/mL | Standard Deviation 0.491 |
| ESRD Dose After Hemodialysis | Mean Peak Anti-FXa Activity Following a Single Oral Dose of 5 mg Apixaban | 1.29 IU/mL | Standard Deviation 0.579 |
Other Pre-specified
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.
Time frame: From Day 1 to 30 days post study discontinuation
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Normal Renal Function | Number of Participants Who Died or Experienced Serious Adverse Events (SAEs) or Adverse Events Leading to Discontinuation | Deaths | 0 participants |
| Normal Renal Function | Number of Participants Who Died or Experienced Serious Adverse Events (SAEs) or Adverse Events Leading to Discontinuation | SAEs | 0 participants |
| Normal Renal Function | Number of Participants Who Died or Experienced Serious Adverse Events (SAEs) or Adverse Events Leading to Discontinuation | AEs leading to discontinuation | 0 participants |
| ESRD Dose Before Hemodialysis | Number of Participants Who Died or Experienced Serious Adverse Events (SAEs) or Adverse Events Leading to Discontinuation | Deaths | 0 participants |
| ESRD Dose Before Hemodialysis | Number of Participants Who Died or Experienced Serious Adverse Events (SAEs) or Adverse Events Leading to Discontinuation | SAEs | 0 participants |
| ESRD Dose Before Hemodialysis | Number of Participants Who Died or Experienced Serious Adverse Events (SAEs) or Adverse Events Leading to Discontinuation | AEs leading to discontinuation | 0 participants |
Other Pre-specified
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).
Time frame: From 24 hours pre-dose to 72 hours post-dose
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Normal Renal Function | Number of Participants With Laboratory Marked Abnormalities | BUN | 0 participants |
| Normal Renal Function | Number of Participants With Laboratory Marked Abnormalities | Platelet count | 0 participants |
| Normal Renal Function | Number of Participants With Laboratory Marked Abnormalities | Creatine | 0 participants |
| Normal Renal Function | Number of Participants With Laboratory Marked Abnormalities | Potassium | 0 participants |
| Normal Renal Function | Number of Participants With Laboratory Marked Abnormalities | Phosphorus | 0 participants |
| Normal Renal Function | Number of Participants With Laboratory Marked Abnormalities | Lactate dehydrogenase | 0 participants |
| ESRD Dose Before Hemodialysis | Number of Participants With Laboratory Marked Abnormalities | Phosphorus | 1 participants |
| ESRD Dose Before Hemodialysis | Number of Participants With Laboratory Marked Abnormalities | BUN | 4 participants |
| ESRD Dose Before Hemodialysis | Number of Participants With Laboratory Marked Abnormalities | Potassium | 1 participants |
| ESRD Dose Before Hemodialysis | Number of Participants With Laboratory Marked Abnormalities | Platelet count | 1 participants |
| ESRD Dose Before Hemodialysis | Number of Participants With Laboratory Marked Abnormalities | Lactate dehydrogenase | 1 participants |
| ESRD Dose Before Hemodialysis | Number of Participants With Laboratory Marked Abnormalities | Creatine | 1 participants |