Trial Outcomes & Findings for Pharmacokinetics and Pharmacodynamics of Apixaban in Subjects on Hemodialysis (NCT NCT01340586)

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).

Pharmacokinetics and Pharmacodynamics of Apixaban in Subjects on Hemodialysis

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).

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).

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).

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).

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).

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).

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) for BMS-730823 was derived from plasma concentrations versus time data.

Time of maximum observed plasma concentration (Tmax) for apixaban was derived from plasma concentrations versus time data. Medians were reported in hours.

Time of maximum observed plasma concentration (Tmax) for BMS-730823 was derived from plasma concentrations versus time data. Medians were reported in hours.

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.

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.

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.

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.

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).

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).

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).

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).

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.

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.

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.

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.

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.

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).

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).

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.