A Phase 1 interventional study of Warfarin (Coumadin) and Rivaroxaban (Xarelto, BAY59-7939) in Venous Thrombosis, sponsored by Bayer. Completed at 2 sites in Germany. Open to male participants aged 18 Years to 45 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2015-02-09.
Sponsored by Bayer · Phase 1 and Interventional
The study objective is to investigate the pharmacodynamics (effects of a drug product) when switching the treatment from warfarin to rivaroxaban.
84 young, healthy subjects will participate; they will be treated following a randomized, parallel-group (Treatments A, B, and C), placebo-controlled (Treatment B), and single-blind (Treatments A and B) design.
The first two groups (A, B) will receive warfarin for approximately one week to adjust their blood coagulation values to a specific level, i.e. to maintain an INR (international normalized ratio) of 2.0 - 3.0. This range is commonly used for long-term anticoagulant treatment.
The first group (A) will receive rivaroxaban for four days, the second group (B) will take placebo. On the last day, all subjects in groups A and B will receive vitamin K to neutralize the effects of warfarin. The third group (C) will not undergo prior treatment with warfarin but will receive rivaroxaban for four days.
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Exclusion Criteria:
Days -6 and -5: 10 mg warfarin once daily or lower depending on international normalized ratio (INR); Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily
Drug: Warfarin (Coumadin) · Drug: Rivaroxaban (Xarelto, BAY59-7939) · Drug: Vitamin K (Konakion)
Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily
Drug: Warfarin (Coumadin) · Drug: Placebo · Drug: Vitamin K (Konakion)
Days 0 to 3: 20 mg rivaroxaban once daily
Drug: Rivaroxaban (Xarelto, BAY59-7939)
Days -6 and -5: 10 mg warfarin (Coumadin) once daily, dosage lower if the INR is already high on day -5; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin (Coumadin) once daily, dosage depending on INR
Days 0 to 3: 20 mg rivaroxaban once daily
Days 0 to 3: 1 tablet placebo, identical to active tablet
Day 5: 10 mg vitamin K (Konakion) once daily
Emax (Maximum Effect) on Prothrombin Time (PT) (Coagulation Test)
Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Higher values than the baseline indicate anticoagulant effects. Emax on PT was measured as the ratio of maximum PT (measured in seconds) divided by PT (measured in seconds) at baseline.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Emax,BA (Baseline Adjusted Maximum Effect) on Prothrombin Time (Coagulation Test)
Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Higher values than the baseline indicate anticoagulant effects. Emax,BA on PT was measured as maximum PT (measured in seconds) minus PT (measured in seconds) at baseline.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Prothrombin Time (Coagulation Test)
Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of PT was the area under the measurement (PT \[measured in seconds\] at different time-points divided by PT \[measured in seconds\] at baseline) versus time curve from time 0 to the last data point.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
AUCBA(0-tn) (Baseline Adjusted Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Prothrombin Time (Coagulation Test)
Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Higher values than the baseline indicate anticoagulant effects. AUCBA(0-tn) of PT was the area under the measurement (PT \[measured in seconds\] at different time-points minus PT \[measured in seconds\] at baseline) versus time curve from time 0 to the last data point.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Emax on PT (Measured as INR=International Normalized Ratio)
Prothrombin time - INR measured in seconds that is calculated as INR which is a correction for PT assay differences and an optimization to measure vitamin K antagonists. Higher values than the baseline indicate anticoagulant effects. Emax on PT (INR) was measured as the ratio of maximum INR divided by baseline INR.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) for PT (Measured as INR=International Normalized Ratio)
Prothrombin time - INR measured in seconds that is calculated as INR which is a correction for PT assay differences and an optimization to measure vitamin K antagonists. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of PT (INR) was the area under the measurement (PT measured as INR at different time-points divided by PT measured as INR at baseline) versus time curve from time 0 to the last data point.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Emax on Factor Xa Activity
Test to measure the activity of endogenous Factor Xa. Emax on Factor Xa activity was calculated as 100\*(Factor Xa activity at baseline \[measured as activity per mL\] - minimum of Factor Xa activity \[measured as activity per mL\]) / Factor Xa activity at baseline \[measured as activity per mL\].
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
AUC(0-tn) (Area Under the Inverse Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor Xa Activity
Test to measure the activity of endogenous Factor Xa. AUC(0-tn) of Factor Xa activity was the area under the inverse measurement \[100\*(Factor Xa activity at baseline (measured as activity per mL) - Factor Xa activity (measured as activity per mL) at different time-points) / Factor Xa activity at baseline (measured as activity per mL)\] versus time curve from time 0 to the last data point.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Emax (Maximum Effect) on Anti-Factor Xa Activity
This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. Higher Values than the baseline indicate a more pronounced inhibition. Emax on anti-Factor Xa activity was measured as the ratio of maximum anti-Factor Xa activity (measured in U/L) divided by anti-Factor Xa activity (measured in U/L) at baseline.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Anti-Factor Xa Activity
This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. Higher Values than the baseline indicate a more pronounced inhibition. AUC(0-tn) of anti-Factor Xa activity was the area under the measurement (anti-Factor Xa activity \[measured in U/L\] at different time-points divided by anti-Factor Xa activity \[measured in U/L\] at baseline) versus time curve from time 0 to the last data point.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Emax (Maximum Effect) on aPTT (Activated Partial Thromboplastin Time)
The aPTT is a screening test for the intrinsic pathway and is sensitive for deficiencies of Factors I, II, V, VIII, IX, X, XI and XII. Higher values than the baseline indicate anticoagulant effects. Emax on aPTT was measured as the ratio of maximum aPTT (measured in seconds) divided by aPTT (measured in seconds) at baseline.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of aPTT (Activated Partial Thromboplastin Time)
The aPTT is a screening test for the intrinsic pathway and is sensitive for deficiencies of Factors I, II, V, VIII, IX, X, XI and XII. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of aPTT was the area under the measurement (aPTT \[measured in seconds\] at different time-points divided by aPTT \[measured in seconds\] at baseline) versus time curve from time 0 to the last data point.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Emax (Maximum Effect) on HepTest (Coagulation Test)
This coagulation test was developed to monitor heparin and especially low-molecular weight heparins (LMWH). It is sensitive to measure Factor X. Higher values than the baseline indicate anticoagulant effects. Emax on HepTest was measured as the ratio of maximum HepTest (measured in seconds) divided by HepTest (measured in seconds) at baseline.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of HepTest (Coagulation Test)
This coagulation test was developed to monitor heparin and especially low-molecular weight heparins (LMWH). It is sensitive to measure Factor X. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of HepTest was the area under the measurement (HepTest \[measured in seconds\] at different time-points divided by HepTest \[measured in seconds\] at baseline) versus time curve from time 0 to the last data point.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Emax (Maximum Effect) on PiCT (Prothrombinase-induced Clotting Time)
This coagulation test can be adapted to measure different anticoagulants, including inhibitors of Factor X. Higher values than the baseline indicate anticoagulant effects. Emax on PiCT was measured as the ratio of maximum PiCT (measured in seconds) divided by PiCT (measured in seconds) at baseline.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of PiCT (Prothrombinase-induced Clotting Time)
This coagulation test can be adapted to measure different anticoagulants, including inhibitors of Factor X. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of PiCT was the area under the measurement (PiCT \[measured in seconds\] at different time-points divided by PiCT \[measured in seconds\] at baseline) versus time curve from time 0 to the last data point.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) AUC
ETP AUC assesses the overall function of the clotting cascade. The AUC assesses the overall ability to generate thrombin. Decreasing values compared to baseline indicate an anticoagulant effect. Emax on ETP AUC was measured as the ratio of ETP AUC (measured in nm\*min as integral of fluorescence measurements) at baseline divided by minimum ETP AUC (measured in nm\*min as integral of fluorescence measurements).
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) AUC
ETP AUC assesses the overall function of the clotting cascade. The AUC assesses the overall ability to generate thrombin. Decreasing values compared to baseline indicate an anticoagulant effect. AUC(0-tn) of ETP AUC was the area under the measurement (ETP AUC \[measured in nm\*min as integral of fluorescence measurements\] at baseline divided by ETP AUC \[measured in nm\*min as integral of fluorescence measurements\] at different time-points) versus time curve from time 0 to the last data point.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Lag Time
ETP lag time assesses the overall function of the clotting cascade. The lag time assesses the time required until thrombin is generated. Increasing values compared to baseline indicate an anticoagulant effect. Emax on ETP lag time was measured as the ratio of maximum ETP lag time (in minutes as measure for the start of coagulation) divided by ETP lag time (in minutes as measure for the start of coagulation) at baseline.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) Lag Time
ETP lag time assesses the overall function of the clotting cascade. The lag time assesses the time required until thrombin is generated. Increasing values compared to baseline indicate an anticoagulant effect. AUC(0-tn) of ETP lag time was the area under the measurement (ETP lag time \[in minutes as measure for the start of coagulation\] at different time-points divided by ETP lag time \[in minutes as measure for the start of coagulation\] at baseline) versus time curve from time 0 to the last data point.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak
ETP peak assesses the overall function of the clotting cascade. The peak assesses the overall maximal ability to generate thrombin. Decreasing values compared to baseline indicate an anticoagulant effect. Emax on ETP peak was measured as the ratio of ETP peak (measured in nm as maximum coagulation activity) at baseline divided by minimum ETP peak (measured in nm as maximum coagulation activity).
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) Peak
ETP peak assesses the overall function of the clotting cascade. The peak assesses the overall maximal ability to generate thrombin. Decreasing values compared to baseline indicate an anticoagulant effect. AUC(0-tn) of ETP peak was the area under the measurement (ETP peak \[measured in nm as maximum coagulation activity\] at baseline divided by ETP peak measured \[in nm as maximum coagulation activity\] at different time-points) versus time curve from time 0 to the last data point.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak Time
ETP peak time assesses the overall function of the clotting cascade. The peak time assesses the time required to reach the maximal thrombin generation. Increasing values compared to baseline indicate an anticoagulant effect. Emax on ETP peak time was measured as the ratio of maximum ETP peak time (measured in minutes as time to reach the maximum coagulation activity) divided by ETP peak time (measured in minutes as time to reach the maximum coagulation activity) at baseline.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) Peak Time
ETP peak time assesses the overall function of the clotting cascade. The peak time assesses the time required to reach the maximal thrombin generation. Increasing values compared to baseline indicate an anticoagulant effect. AUC(0-tn) of ETP peak time was the area under the measurement (ETP peak time \[measured in minutes as time to reach the maximum coagulation activity\] at different time-points divided by ETP peak time \[measured in minutes as time to reach the maximum coagulation activity\] at baseline) versus time curve from time 0 to the last data point.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Emax (Maximum Effect) on Factor VIIa Activity
Factor VII is a coagulation factor that is required for the coagulation process. Emax on Factor VIIa activity was measured as the ratio of Factor VIIa activity (measured as percent of actual Factor VIIa activity compared to Factor VIIa activity in reference plasma) at baseline divided by minimum Factor VIIa activity (measured as percent of actual Factor VIIa activity compared to Factor VIIa activity in reference plasma).
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor VIIa Activity
Factor VII is a coagulation factor that is required for the coagulation process. AUC(0-tn) of Factor VIIa activity was the area under the measurement (Factor VIIa activity \[measured as percent of actual Factor VIIa activity compared to Factor VIIa activity in reference plasma\] at baseline divided by Factor VIIa activity \[measured as percent of actual Factor VIIa activity compared to Factor VIIa activity in reference plasma\] at different time-points) versus time curve from time 0 to the last data point.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Emax (Maximum Effect) on Factor IIa Activity
Factor II (Thrombin) is a coagulation factor that is required for the coagulation process. Emax on Factor IIa activity was measured as the ratio of Factor IIa activity (measured as percent of actual Factor IIa activity compared to Factor IIa activity in reference plasma) at baseline divided by minimum Factor IIa activity (measured as percent of actual Factor IIa activity compared to Factor IIa activity in reference plasma).
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor IIa Activity
Factor II (Thrombin) is a coagulation factor that is required for the coagulation process. AUC(0-tn) of Factor IIa activity was the area under the measurement (Factor IIa activity \[measured as percent of actual Factor IIa activity compared to Factor IIa activity in reference plasma\] at baseline divided by Factor IIa activity \[measured as percent of actual Factor IIa activity compared to Factor IIa activity in reference plasma\] at different time-points) versus time curve from time 0 to the last data point.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours [AUC(0-24)] of Rivaroxaban After First Dose
The AUC is a measure of systemic drug exposure which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample (\[AUC(0-24)\] is defined as area under the concentration vs. time curve from zero to 24 hours after first (single) dose).
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Maximum Drug Concentration in Plasma (Cmax) of Rivaroxaban After First Dose
Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Half Life Associated With Terminal Slope (t1/2) of R-warfarin After the Last Dose of Warfarin
Half-life refers to the elimination of the drug, i.e. the time it takes for the blood plasma concentration to reach half the concentration in the terminal phase of elimination.
Time frame: Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration of warfarin
Half Life Associated With Terminal Slope (t1/2) of S-warfarin After the Last Dose of Warfarin
Half-life refers to the elimination of the drug, i.e. the time it takes for the blood plasma concentration to reach half the concentration in the terminal phase of elimination.
Time frame: Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration of warfarin
Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Divided by Dose Per kg Body Weight [AUC(0-24)Norm] of Rivaroxaban After First Dose
The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample; \[AUC(0-24)norm\] is defined as AUC divided by dose per kg body weight from zero to 24 hours after first (single) dose.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Maximum Drug Concentration in Plasma Divided by Dose Per kg Body Weight (Cmax,Norm) of Rivaroxaban After First Dose
Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample; Cmax,norm is defined as Cmax divided by dose (mg) per kg body weight.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Rivaroxaban After First Dose
Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban
Drug Concentration in Plasma at Expected Time of Maximum (Peak) Concentration (Cpeak) of Rivaroxaban After Second to Fourth Dose
Cpeak refers to the time after dosing when the drug concentration is expected to reach its maximum (peak) concentration.
Time frame: Always 3 h after second, third, and fourth dose
Drug Concentration in Plasma at Expected Time of Minimum (Trough) Concentration (Ctrough) of Rivaroxaban After Second to Fourth Dose
Ctrough refers to the time after dosing when the drug concentration is expected to reach its minimum (trough) concentration.
Time frame: Always 24 h after the second, third, and fourth dose
Half Life Associated With Terminal Slope (t1/2) of Rivaroxaban After Last Dose
Half-life refers to the elimination of the drug, i.e. the time it takes for the blood plasma concentration to reach half the concentration in the terminal phase of elimination.
Time frame: 3, 24, 48, and 72 h after the last administration of rivaroxaban
Drug Concentration in Plasma at Steady State at Expected Time of Minimum (Trough) Concentration (Ctrough,ss) of R-warfarin After the Last Dose of Warfarin
Ctrough,ss refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration.
Time frame: 0 h (predose) and 24 h after the last administration of warfarin
Drug Concentration in Plasma at Steady State at Expected Time of Minimum (Trough) Concentration, Normalized by Dose (Ctrough,ss/D) of R-warfarin After the Last Dose of Warfarin
Ctrough,ss/D refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration, normalized by dose.
Time frame: 0 h (predose) and 24 h after the last administration of warfarin
Drug Concentration in Plasma at Steady State at Expected Time of Minimum (Trough) Concentration (Ctrough,ss) of S-warfarin After the Last Dose of Warfarin
Ctrough,ss refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration.
Time frame: 0 h (predose) and 24 h after the last administration of warfarin
Drug Concentration in Plasma at Steady State at Expected Time of Minimum (Trough) Concentration, Normalized by Dose (Ctrough,ss/D) of S-warfarin After the Last Dose of Warfarin
Ctrough,ss/D refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration, normalized by dose.
Time frame: 0 h (predose) and 24 h after the last administration of warfarin
Participants were recruited by 2 centers in Germany: ClinPharmCologne - MEDA Manufacturing GmbH, Neurather Ring 1, 51063 Koeln, and CRS Clinical-Research-Services Moenchengladbach GmbH, Hindenburgstrasse 304-306, 41061 Moenchengladbach. 84 participants were planned to participate (n=28 per group; minimum completion target n=75, n=25 per group).
| Milestone | Group A: Warfarin Followed by Rivaroxaban | Group B: Warfarin Followed by Placebo | Group C: Rivaroxaban Without Any Pre-treatment With Warfarin | Group D: Warfarin Alone |
|---|---|---|---|---|
| Started | 29 | 31 | 29 | 7 |
| Warfarin run-in phase | 28 | 28 | 0 | 7 |
| Received placebo or rivaroxaban | 28 | 28 | 28 | 0 |
| Completed | 27 | 28 | 28 | 0 |
| Not completed | 2 | 3 | 1 | 7 |
| Withdrew: Withdrawal by subject | 1 | 3 | 1 | 6 |
| Withdrew: Physician decision | 0 | 0 | 0 | 1 |
| Withdrew: Adverse event | 1 | 0 | 0 | 0 |
Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Higher values than the baseline indicate anticoagulant effects. Emax on PT was measured as the ratio of maximum PT (measured in seconds) divided by PT (measured in seconds) at baseline.
| ratio | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| Emax (Maximum Effect) on Prothrombin Time (PT) (Coagulation Test) | 4.393 ± 18.03 | 1.884 ± 10.35 | 1.573 ± 9.98 |
Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Higher values than the baseline indicate anticoagulant effects. Emax,BA on PT was measured as maximum PT (measured in seconds) minus PT (measured in seconds) at baseline.
| seconds | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| Emax,BA (Baseline Adjusted Maximum Effect) on Prothrombin Time (Coagulation Test) | 44.98 ± 20.84 | 11.59 ± 19.52 | 7.31 ± 23.72 |
Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of PT was the area under the measurement (PT \[measured in seconds\] at different time-points divided by PT \[measured in seconds\] at baseline) versus time curve from time 0 to the last data point.
| ratio*h | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Prothrombin Time (Coagulation Test) | 55.36 ± 13.36 | 37.89 ± 9.92 | 20.41 ± 33.52 |
Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Higher values than the baseline indicate anticoagulant effects. AUCBA(0-tn) of PT was the area under the measurement (PT \[measured in seconds\] at different time-points minus PT \[measured in seconds\] at baseline) versus time curve from time 0 to the last data point.
| s*h | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| AUCBA(0-tn) (Baseline Adjusted Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Prothrombin Time (Coagulation Test) | 413.4 ± 19.87 | 179.9 ± 26.58 | 33.06 ± 55.70 |
Prothrombin time - INR measured in seconds that is calculated as INR which is a correction for PT assay differences and an optimization to measure vitamin K antagonists. Higher values than the baseline indicate anticoagulant effects. Emax on PT (INR) was measured as the ratio of maximum INR divided by baseline INR.
| ratio | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| Emax on PT (Measured as INR=International Normalized Ratio) | 6.655 ± 23.39 | 2.250 ± 13.19 | 1.793 ± 12.87 |
Prothrombin time - INR measured in seconds that is calculated as INR which is a correction for PT assay differences and an optimization to measure vitamin K antagonists. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of PT (INR) was the area under the measurement (PT measured as INR at different time-points divided by PT measured as INR at baseline) versus time curve from time 0 to the last data point.
| ratio*h | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) for PT (Measured as INR=International Normalized Ratio) | 72.30 ± 17.35 | 43.60 ± 12.81 | 23.21 ± 30.63 |
Test to measure the activity of endogenous Factor Xa. Emax on Factor Xa activity was calculated as 100\*(Factor Xa activity at baseline \[measured as activity per mL\] - minimum of Factor Xa activity \[measured as activity per mL\]) / Factor Xa activity at baseline \[measured as activity per mL\].
| Percentage of inhibition | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| Emax on Factor Xa Activity | 75.95 ± 6.56 | 43.41 ± 12.67 | 49.73 ± 13.86 |
Test to measure the activity of endogenous Factor Xa. AUC(0-tn) of Factor Xa activity was the area under the inverse measurement \[100\*(Factor Xa activity at baseline (measured as activity per mL) - Factor Xa activity (measured as activity per mL) at different time-points) / Factor Xa activity at baseline (measured as activity per mL)\] versus time curve from time 0 to the last data point.
| Percentage of inhibition*h | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| AUC(0-tn) (Area Under the Inverse Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor Xa Activity | 1238 ± 12.28 | 834.8 ± 19.44 | 514.1 ± 27.90 |
This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. Higher Values than the baseline indicate a more pronounced inhibition. Emax on anti-Factor Xa activity was measured as the ratio of maximum anti-Factor Xa activity (measured in U/L) divided by anti-Factor Xa activity (measured in U/L) at baseline.
| ratio | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| Emax (Maximum Effect) on Anti-Factor Xa Activity | 15.83 ± 56.06 | 2.281 ± 112.7 | 18.57 ± 42.99 |
This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. Higher Values than the baseline indicate a more pronounced inhibition. AUC(0-tn) of anti-Factor Xa activity was the area under the measurement (anti-Factor Xa activity \[measured in U/L\] at different time-points divided by anti-Factor Xa activity \[measured in U/L\] at baseline) versus time curve from time 0 to the last data point.
| ratio*h | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Anti-Factor Xa Activity | 124.9 ± 68.84 | 19.63 ± 202.0 | 151.6 ± 38.88 |
The aPTT is a screening test for the intrinsic pathway and is sensitive for deficiencies of Factors I, II, V, VIII, IX, X, XI and XII. Higher values than the baseline indicate anticoagulant effects. Emax on aPTT was measured as the ratio of maximum aPTT (measured in seconds) divided by aPTT (measured in seconds) at baseline.
| ratio | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| Emax (Maximum Effect) on aPTT (Activated Partial Thromboplastin Time) | 1.843 ± 10.55 | 1.304 ± 15.07 | 1.409 ± 6.19 |
The aPTT is a screening test for the intrinsic pathway and is sensitive for deficiencies of Factors I, II, V, VIII, IX, X, XI and XII. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of aPTT was the area under the measurement (aPTT \[measured in seconds\] at different time-points divided by aPTT \[measured in seconds\] at baseline) versus time curve from time 0 to the last data point.
| ratio*h | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of aPTT (Activated Partial Thromboplastin Time) | 32.48 ± 9.41 | 22.55 ± 56.41 | 21.82 ± 42.67 |
This coagulation test was developed to monitor heparin and especially low-molecular weight heparins (LMWH). It is sensitive to measure Factor X. Higher values than the baseline indicate anticoagulant effects. Emax on HepTest was measured as the ratio of maximum HepTest (measured in seconds) divided by HepTest (measured in seconds) at baseline.
| ratio | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| Emax (Maximum Effect) on HepTest (Coagulation Test) | 2.148 ± 14.20 | 1.163 ± 19.78 | 2.009 ± 12.13 |
This coagulation test was developed to monitor heparin and especially low-molecular weight heparins (LMWH). It is sensitive to measure Factor X. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of HepTest was the area under the measurement (HepTest \[measured in seconds\] at different time-points divided by HepTest \[measured in seconds\] at baseline) versus time curve from time 0 to the last data point.
| ratio*h | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of HepTest (Coagulation Test) | 27.37 ± 32.90 | 15.08 ± 125.9 | 28.25 ± 29.31 |
This coagulation test can be adapted to measure different anticoagulants, including inhibitors of Factor X. Higher values than the baseline indicate anticoagulant effects. Emax on PiCT was measured as the ratio of maximum PiCT (measured in seconds) divided by PiCT (measured in seconds) at baseline.
| ratio | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| Emax (Maximum Effect) on PiCT (Prothrombinase-induced Clotting Time) | 3.158 ± 27.20 | 1.139 ± 21.36 | 2.723 ± 20.69 |
This coagulation test can be adapted to measure different anticoagulants, including inhibitors of Factor X. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of PiCT was the area under the measurement (PiCT \[measured in seconds\] at different time-points divided by PiCT \[measured in seconds\] at baseline) versus time curve from time 0 to the last data point.
| ratio*h | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of PiCT (Prothrombinase-induced Clotting Time) | 37.36 ± 38.40 | 4.221 ± 429.5 | 39.20 ± 8.91 |
ETP AUC assesses the overall function of the clotting cascade. The AUC assesses the overall ability to generate thrombin. Decreasing values compared to baseline indicate an anticoagulant effect. Emax on ETP AUC was measured as the ratio of ETP AUC (measured in nm\*min as integral of fluorescence measurements) at baseline divided by minimum ETP AUC (measured in nm\*min as integral of fluorescence measurements).
| ratio | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) AUC | 4.257 ± 24.41 | 2.610 ± 22.05 | 1.813 ± 25.45 |
ETP AUC assesses the overall function of the clotting cascade. The AUC assesses the overall ability to generate thrombin. Decreasing values compared to baseline indicate an anticoagulant effect. AUC(0-tn) of ETP AUC was the area under the measurement (ETP AUC \[measured in nm\*min as integral of fluorescence measurements\] at baseline divided by ETP AUC \[measured in nm\*min as integral of fluorescence measurements\] at different time-points) versus time curve from time 0 to the last data point.
| ratio*h | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) AUC | 69.69 ± 25.83 | 51.28 ± 17.90 | 18.06 ± 78.12 |
ETP lag time assesses the overall function of the clotting cascade. The lag time assesses the time required until thrombin is generated. Increasing values compared to baseline indicate an anticoagulant effect. Emax on ETP lag time was measured as the ratio of maximum ETP lag time (in minutes as measure for the start of coagulation) divided by ETP lag time (in minutes as measure for the start of coagulation) at baseline.
| ratio | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Lag Time | 3.954 ± 19.02 | 1.748 ± 18.49 | 2.569 ± 9.83 |
ETP lag time assesses the overall function of the clotting cascade. The lag time assesses the time required until thrombin is generated. Increasing values compared to baseline indicate an anticoagulant effect. AUC(0-tn) of ETP lag time was the area under the measurement (ETP lag time \[in minutes as measure for the start of coagulation\] at different time-points divided by ETP lag time \[in minutes as measure for the start of coagulation\] at baseline) versus time curve from time 0 to the last data point.
| ratio*h | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) Lag Time | 63.75 ± 17.88 | 34.93 ± 20.83 | 42.79 ± 9.54 |
ETP peak assesses the overall function of the clotting cascade. The peak assesses the overall maximal ability to generate thrombin. Decreasing values compared to baseline indicate an anticoagulant effect. Emax on ETP peak was measured as the ratio of ETP peak (measured in nm as maximum coagulation activity) at baseline divided by minimum ETP peak (measured in nm as maximum coagulation activity).
| ratio | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak | 18.73 ± 44.08 | 2.523 ± 44.17 | 6.758 ± 33.31 |
ETP peak assesses the overall function of the clotting cascade. The peak assesses the overall maximal ability to generate thrombin. Decreasing values compared to baseline indicate an anticoagulant effect. AUC(0-tn) of ETP peak was the area under the measurement (ETP peak \[measured in nm as maximum coagulation activity\] at baseline divided by ETP peak measured \[in nm as maximum coagulation activity\] at different time-points) versus time curve from time 0 to the last data point.
| ratio*h | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) Peak | 166.8 ± 45.97 | 46.75 ± 19.22 | 74.67 ± 27.40 |
ETP peak time assesses the overall function of the clotting cascade. The peak time assesses the time required to reach the maximal thrombin generation. Increasing values compared to baseline indicate an anticoagulant effect. Emax on ETP peak time was measured as the ratio of maximum ETP peak time (measured in minutes as time to reach the maximum coagulation activity) divided by ETP peak time (measured in minutes as time to reach the maximum coagulation activity) at baseline.
| ratio | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak Time | 4.164 ± 33.95 | 1.375 ± 20.87 | 3.790 ± 15.75 |
ETP peak time assesses the overall function of the clotting cascade. The peak time assesses the time required to reach the maximal thrombin generation. Increasing values compared to baseline indicate an anticoagulant effect. AUC(0-tn) of ETP peak time was the area under the measurement (ETP peak time \[measured in minutes as time to reach the maximum coagulation activity\] at different time-points divided by ETP peak time \[measured in minutes as time to reach the maximum coagulation activity\] at baseline) versus time curve from time 0 to the last data point.
| ratio*h | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) Peak Time | 49.14 ± 28.10 | 19.83 ± 143.9 | 55.58 ± 12.47 |
Factor VII is a coagulation factor that is required for the coagulation process. Emax on Factor VIIa activity was measured as the ratio of Factor VIIa activity (measured as percent of actual Factor VIIa activity compared to Factor VIIa activity in reference plasma) at baseline divided by minimum Factor VIIa activity (measured as percent of actual Factor VIIa activity compared to Factor VIIa activity in reference plasma).
| ratio | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| Emax (Maximum Effect) on Factor VIIa Activity | 12.80 ± 47.88 | 6.769 ± 53.51 | 1.346 ± 7.51 |
Factor VII is a coagulation factor that is required for the coagulation process. AUC(0-tn) of Factor VIIa activity was the area under the measurement (Factor VIIa activity \[measured as percent of actual Factor VIIa activity compared to Factor VIIa activity in reference plasma\] at baseline divided by Factor VIIa activity \[measured as percent of actual Factor VIIa activity compared to Factor VIIa activity in reference plasma\] at different time-points) versus time curve from time 0 to the last data point.
| ratio*h | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor VIIa Activity | 134.2 ± 44.70 | 94.83 ± 41.07 | 9.283 ± 70.62 |
Factor II (Thrombin) is a coagulation factor that is required for the coagulation process. Emax on Factor IIa activity was measured as the ratio of Factor IIa activity (measured as percent of actual Factor IIa activity compared to Factor IIa activity in reference plasma) at baseline divided by minimum Factor IIa activity (measured as percent of actual Factor IIa activity compared to Factor IIa activity in reference plasma).
| ratio | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| Emax (Maximum Effect) on Factor IIa Activity | 3.166 ± 16.09 | 2.958 ± 12.31 | 1.126 ± 5.08 |
Factor II (Thrombin) is a coagulation factor that is required for the coagulation process. AUC(0-tn) of Factor IIa activity was the area under the measurement (Factor IIa activity \[measured as percent of actual Factor IIa activity compared to Factor IIa activity in reference plasma\] at baseline divided by Factor IIa activity \[measured as percent of actual Factor IIa activity compared to Factor IIa activity in reference plasma\] at different time-points) versus time curve from time 0 to the last data point.
| ratio*h | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor IIa Activity | 62.26 ± 18.20 | 58.60 ± 15.18 | 3.908 ± 117.7 |
The AUC is a measure of systemic drug exposure which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample (\[AUC(0-24)\] is defined as area under the concentration vs. time curve from zero to 24 hours after first (single) dose).
| microg*h/L | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours [AUC(0-24)] of Rivaroxaban After First Dose | 1639 ± 29.46 | 1722 ± 26.19 |
Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample.
| microg/L | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|
| Maximum Drug Concentration in Plasma (Cmax) of Rivaroxaban After First Dose | 219.8 ± 30.94 | 221.0 ± 26.65 |
Half-life refers to the elimination of the drug, i.e. the time it takes for the blood plasma concentration to reach half the concentration in the terminal phase of elimination.
| hours | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo |
|---|---|---|
| Half Life Associated With Terminal Slope (t1/2) of R-warfarin After the Last Dose of Warfarin | 40.08 ± 19.63 | 40.24 ± 29.43 |
Half-life refers to the elimination of the drug, i.e. the time it takes for the blood plasma concentration to reach half the concentration in the terminal phase of elimination.
| hours | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo |
|---|---|---|
| Half Life Associated With Terminal Slope (t1/2) of S-warfarin After the Last Dose of Warfarin | 28.24 ± 17.95 | 27.08 ± 22.79 |
The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample; \[AUC(0-24)norm\] is defined as AUC divided by dose per kg body weight from zero to 24 hours after first (single) dose.
| Kg*h/L | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Divided by Dose Per kg Body Weight [AUC(0-24)Norm] of Rivaroxaban After First Dose | 6.569 ± 27.55 | 6.901 ± 31.63 |
Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample; Cmax,norm is defined as Cmax divided by dose (mg) per kg body weight.
| Kg/L | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|
| Maximum Drug Concentration in Plasma Divided by Dose Per kg Body Weight (Cmax,Norm) of Rivaroxaban After First Dose | 0.8812 ± 27.83 | 0.8857 ± 31.79 |
Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.
| hours | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|
| Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Rivaroxaban After First Dose | 3.008 (1.000 to 4.000) | 3.000 (1.000 to 4.067) |
Cpeak refers to the time after dosing when the drug concentration is expected to reach its maximum (peak) concentration.
| Microg/L | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|
| second dose | 211.2 ± 28.72 | 206.7 ± 35.62 |
| third dose | 206.1 ± 30.66 | 201.0 ± 30.65 |
| fourth dose | 201.4 ± 77.43 | 214.5 ± 27.35 |
Ctrough refers to the time after dosing when the drug concentration is expected to reach its minimum (trough) concentration.
| Microg/L | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|
| second dose | 13.06 ± 50.64 | 17.07 ± 45.32 |
| third dose | 14.34 ± 54.05 | 15.85 ± 47.92 |
| fourth dose | 12.43 ± 85.96 | 15.61 ± 51.52 |
Half-life refers to the elimination of the drug, i.e. the time it takes for the blood plasma concentration to reach half the concentration in the terminal phase of elimination.
| hours | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|
| Half Life Associated With Terminal Slope (t1/2) of Rivaroxaban After Last Dose | 6.885 ± 42.48 | 6.931 ± 36.70 |
Ctrough,ss refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration.
| Microg/L | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo |
|---|---|---|
| before last administration | 754.4 ± 32.70 | 721.8 ± 25.56 |
| after last administration | 740.2 ± 25.88 | 702.8 ± 28.39 |
Ctrough,ss/D refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration, normalized by dose.
| 1/Liter | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo |
|---|---|---|
| before last administration | 0.07154 ± 40.86 | 0.07843 ± 48.55 |
| after last administration | 0.08633 ± 44.10 | 0.07915 ± 46.50 |
Ctrough,ss refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration.
| Microg/L | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo |
|---|---|---|
| before last administration | 498.2 ± 38.93 | 429.9 ± 31.14 |
| after last administration | 478.4 ± 26.17 | 424.9 ± 29.78 |
Ctrough,ss/D refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration, normalized by dose.
| 1/Liter | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo |
|---|---|---|
| before last administration | 0.04724 ± 43.96 | 0.04671 ± 53.03 |
| after last administration | 0.05580 ± 43.11 | 0.04786 ± 38.96 |
Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| RG1: Warfarin Followed by Rivaroxaban | — | 0/28 (0%) | 14/28 (50%) |
| RG2: Warfarin Followed by Placebo | — | 0/28 (0%) | 12/28 (42.9%) |
| RG3: Rivaroxaban | — | 0/28 (0%) | 10/28 (35.7%) |
| RG4: Warfarin Alone | — | 0/63 (0%) | 21/63 (33.3%) |
| Event | RG1: Warfarin Followed by Rivaroxaban | RG2: Warfarin Followed by Placebo | RG3: Rivaroxaban | RG4: Warfarin Alone |
|---|---|---|---|---|
| NasopharyngitisInfections and infestations | 0/28 | 0/28 | 3/28 | 1/63 |
| Nasal congestionRespiratory, thoracic and mediastinal disorders | 0/28 | 3/28 | 0/28 | 0/63 |
| Abdominal painGastrointestinal disorders | 0/28 | 2/28 | 0/28 | 1/63 |
| DiarrhoeaGastrointestinal disorders | 2/28 | 1/28 | 0/28 | 3/63 |
| Gingival bleedingGastrointestinal disorders | 2/28 | 0/28 | 0/28 | 3/63 |
| Lipase increasedInvestigations | 1/28 | 0/28 | 2/28 | 0/63 |
| MyalgiaMusculoskeletal and connective tissue disorders | 0/28 | 2/28 | 0/28 | 0/63 |
| HeadacheNervous system disorders | 2/28 | 1/28 | 1/28 | 4/63 |
| FatigueGeneral disorders | 1/28 | 0/28 | 0/28 | 3/63 |
| BradycardiaCardiac disorders | 0/28 | 0/28 | 1/28 | 0/63 |
| Age, Continuous(years) | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Alone | Total |
|---|---|---|---|---|---|
| Mean | 31.3 ± 7.2 | 30.7 ± 7.5 | 34.8 ± 8.0 | 34.6 ± 6.9 | 32.4 ± 7.6 |
| Sex: Female, Male(Participants) | Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Followed by Placebo | Rivaroxaban (Xarelto, BAY59-7939) | Warfarin Alone | Total |
|---|---|---|---|---|---|
| Female | 0 | 0 | 0 | 0 | 0 |
| Male | 28 | 28 | 28 | 7 | 91 |
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Studies of the drugs tested here: Warfarin · Rivaroxaban