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Bengt I Eriksson - One of the best experts on this subject based on the ideXlab platform.
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population pharmacokinetics and pharmacodynamics of once and twice daily Rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement
Thrombosis and Haemostasis, 2008Co-Authors: Wolfgang Mueck, Frank Misselwitz, Lars C Borris, Ola E Dahl, Sylvia Haas, Menno V Huisman, Ajay K Kakkar, Peter Kalebo, Eva Muelhofer, Bengt I ErikssonAbstract:Rivaroxaban (Xarelto) is an oral, direct factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. The aim was to compare the population pharmacokinetics (PK) and pharmacodynamics (PD) of twice-daily (bid) and once-daily (od) Rivaroxaban in patients undergoing total hip replacement (THR). Blood samples were collected from patients enrolled in two phase IIb, dose-ranging studies undertaken to investigate Rivaroxaban for thromboprophylaxis after THR. A sparse sampling technique was used and the samples were pooled for PK and PD analysis, which used non-linear mixed effect modelling. Rivaroxaban PK (samples from 758 patients) were well described by an oral,one-compartment model; age and renal function influenced clearance, and body surface area affected volume of distribution.When comparing the same total daily doses, maximum plasma concentrations of Rivaroxaban were higher and minimum plasma concentrations were lower with od dosing, compared with bid dosing; however, the 90% intervals overlapped.The area under the plasma concentration–time curve was 18–30% higher in the od than in the bid study. Prothrombin time in seconds (samples from 1181 patients) correlated with Rivaroxaban plasma concentrations in a linear fashion in both studies. In conclusion, the PK and PD of Rivaroxaban were predictable when given either bid or od.These findings, along with the suggested efficacy and safety of Rivaroxaban in the phase II studies, relative to enoxaparin, supported the selection of a convenient, once-daily 10 mg Rivaroxaban dose for investigation in phase III studies.
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population pharmacokinetics and pharmacodynamics of Rivaroxaban an oral direct factor xa inhibitor in patients undergoing major orthopaedic surgery
Clinical Pharmacokinectics, 2008Co-Authors: Wolfgang Mueck, Lars C Borris, Ola E Dahl, Sylvia Haas, Menno V Huisman, Bengt I Eriksson, Kenneth A Bauer, William D Fisher, Michael Gent, Ajay K KakkarAbstract:Background: There is a clinical need for novel oral anticoagulants with predictable pharmacokinetics and pharmacodynamics. Rivaroxaban is an oral direct Factor Xa (FXa) inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. This analysis was performed to characterize the population pharmacokinetics and pharmacodynamics of Rivaroxaban in patients participating in two phase II, double-blind, randomized, active-comparator-controlled studies of twice-daily Rivaroxaban for the prevention of venous thromboembolism after total hip- or knee-replacement surgery. Methods: Sparse blood samples were taken from all patients participating in the studies (n = 1009). In addition, a subset of patients in the hip study (n = 36) underwent full profiling. Rivaroxaban plasma concentrations, FXa activity and the prothrombin time were determined. Nonlinear mixed-effects modelling was used to model the population pharmacokinetics and pharmacodynamics of Rivaroxaban. Results: An oral one-compartment model described the population pharmacokinetics of Rivaroxaban well. On the first postoperative day only, categorization of patients as slow or fast absorbers as a tool to address variability in absorption improved the fit of the model. Clearance of Rivaroxaban was lower and more variable on the first postoperative day, and so time was factored into the model. Overall, the only major difference between the models for the hip study and the knee study was that clearance was 26% lower in the knee study, resulting in approximately 30% higher exposure. Residual variability in the models was moderate (37% and 34% in the hip and knee studies, respectively). Plasma concentrations of Rivaroxaban increased dose dependently. Pharmacokinetic parameters that were estimated using the models agreed closely with results from full-profile patients in the hip study, demonstrating that Rivaroxaban pharmacokinetics are predictable. The pharmacokinetics of Rivaroxaban were affected by expected covariates: age affected clearance in the hip study only, haematocrit (on the first postoperative day only) and gender affected clearance in the knee study only, and renal function affected clearance in both studies. Bodyweight affected the volume of distribution in both studies. However, the effects of covariates on the pharmacokinetics of Rivaroxaban were generally small, and predictions of ‘extreme’ case scenarios suggested that fixed dosing of Rivaroxaban was likely to be possible. FXa activity and the prothrombin time were both affected by surgery, probably because of perioperative bleeding and intravenous administration of fluids; therefore, time was included in the pharmacodynamic models. In both studies, FXa activity correlated with Rivaroxaban plasma concentrations following a maximum effect model, whereas prothrombin time prolongation correlated following a linear model with intercept. The slope of the prothrombin time prolongation correlation was 3.2 seconds/(100 μg/L) in the hip study and 4.2 seconds/(100 μg/L) in the knee study. Both pharmacodynamic models in both studies demonstrated low residual variability of approximately 10%. Conclusion: This population analysis in patients undergoing major orthopaedic surgery demonstrated that Rivaroxaban has predictable, dose-dependent pharmacokinetics that were well described by an oral one-compartment model and affected by expected covariates. Rivaroxaban exposure could be assessed using the prothrombin time, if necessary, but not the international normalized ratio. The findings suggested that fixed dosing of Rivaroxaban may be possible in patients undergoing major orthopaedic surgery.
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dose escalation study of Rivaroxaban bay 59 7939 an oral direct factor xa inhibitor for the prevention of venous thromboembolism in patients undergoing total hip replacement
Thrombosis Research, 2007Co-Authors: Bengt I Eriksson, Frank Misselwitz, Lars C Borris, Ola E Dahl, Sylvia Haas, Menno V Huisman, Ajay K Kakkar, Eva Muehlhofer, Peter KaleboAbstract:Abstract Introduction Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in clinical development for the prevention of thromboembolic disorders. The aim of this study was to demonstrate proof-of-principle for Rivaroxaban. Materials and methods This was an open-label, dose-escalation study to assess the efficacy and safety of Rivaroxaban, relative to enoxaparin, for the prevention of venous thromboembolism (VTE) after total hip replacement surgery. Patients were randomized in a 3:1 ratio to Rivaroxaban (2.5, 5, 10, 20 and 30 mg twice daily [bid] or 30 mg once daily [od] starting 6–8 h after surgery) or enoxaparin (40 mg od starting the evening before surgery). Therapy continued until mandatory bilateral venography was performed 5–9 days after surgery. Results A total of 625 patients received therapy, of whom 466 patients were eligible for the per-protocol efficacy analysis. The primary efficacy endpoint – deep vein thrombosis (DVT), pulmonary embolism (PE) or all-cause mortality – occurred in 22.2%, 23.8%, 20.0%, 10.2%, 17.4%, 15.1% and 16.8% of patients receiving Rivaroxaban 2.5, 5, 10, 20, 30 mg bid, 30 mg od and enoxaparin, respectively. The dose-response relationship with Rivaroxaban for the primary efficacy endpoint was not statistically significant ( p = 0.0504), although major VTE (proximal DVT, PE and VTE-related death) decreased dose dependently with Rivaroxaban ( p = 0.0108). Major, post-operative bleeding increased dose dependently with Rivaroxaban ( p = 0.0008), occurring in 0–10.8% of patients, compared with 0% in patients receiving enoxaparin. Conclusions This study demonstrated proof-of-principle for Rivaroxaban for the prevention of VTE after total hip replacement surgery.
Wolfgang Mueck - One of the best experts on this subject based on the ideXlab platform.
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Clinical Pharmacokinetic and Pharmacodynamic Profile of Rivaroxaban
Clinical Pharmacokinetics, 2014Co-Authors: Wolfgang Mueck, Dagmar Kubitza, Jan Stampfuss, Michael BeckaAbstract:Rivaroxaban is an oral, direct Factor Xa inhibitor that targets free and clot-bound Factor Xa and Factor Xa in the prothrombinase complex. It is absorbed rapidly, with maximum plasma concentrations being reached 2–4 h after tablet intake. Oral bioavailability is high (80–100 %) for the 10 mg tablet irrespective of food intake and for the 15 mg and 20 mg tablets when taken with food. Variability in the pharmacokinetic parameters is moderate (coefficient of variation 30–40 %). The pharmacokinetic profile of Rivaroxaban is consistent in healthy subjects and across a broad range of different patient populations studied. Elimination of Rivaroxaban from plasma occurs with a terminal half-life of 5–9 h in healthy young subjects and 11–13 h in elderly subjects. Rivaroxaban produces a pharmacodynamic effect that is closely correlated with its plasma concentration. The pharmacokinetic and pharmacodynamic relationship for inhibition of Factor Xa activity can be described by an E _max model, and prothrombin time prolongation by a linear model. Rivaroxaban does not inhibit cytochrome P450 enzymes or known drug transporter systems and, because Rivaroxaban has multiple elimination pathways, it has no clinically relevant interactions with most commonly prescribed medications. Rivaroxaban has been approved for clinical use in several thromboembolic disorders.
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erratum to Rivaroxaban population pharmacokinetic analyses in patients treated for acute deep vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention
Clinical Pharmacokinectics, 2011Co-Authors: Wolfgang Mueck, Anthonie W A Lensing, Giancarlo Agnelli, Herve Decousus, Paolo Prandoni, Frank MisselwitzAbstract:BACKGROUND AND OBJECTIVE: Rivaroxaban is an oral, direct Factor Xa inhibitor, which is at an advanced stage of clinical development for prevention and treatment of thromboembolic disorders. Two phase II studies, ODIXa-DVT and EINSTEIN DVT, assessed the efficacy and safety of oral Rivaroxaban (once daily or twice daily) for treatment of acute deep-vein thrombosis (DVT). Population pharmacokinetic and pharmacodynamic analyses of Rivaroxaban in patients in these two phase II studies were conducted to characterize the pharmacokinetics/pharmacodynamics of Rivaroxaban and the relationship between important patient covariates and model parameters. Exposure simulations in patients with atrial fibrillation (AF) were also performed in order to predict the exposure of Rivaroxaban, using modified demographic data reflecting the characteristics of a typical AF population. METHODS: A population pharmacokinetic model was developed using plasma samples from these patients. Various simulations were conducted to explore the pharmacokinetics of Rivaroxaban in patients with DVT and to predict exposure in those with AF. Correlations between plasma Rivaroxaban concentrations and the prothrombin time, Factor Xa activity, HepTest® and activated partial thromboplastin time were also described. RESULTS: The pharmacokinetics of Rivaroxaban in patients with DVT were found to be consistent and predictable across all doses studied. The area under the plasma concentration-time curve (AUC) increased dose dependently. The same total daily doses given once daily achieved higher maximum plasma concentration (C(max)) values (∼20%) and lower trough (minimum) plasma concentration (C(trough)) values (∼60%) than when given twice daily; however, the 5th-95th percentile ranges for these parameters overlapped. Rivaroxaban clearance was moderately influenced by age and renal function, and the volume of distribution was influenced by age, body weight and sex; the effects were within the observed interindividual variability. Simulations in virtual patient populations with AF showed that a Rivaroxaban dose of 15 mg once daily in patients with creatinine clearance of 30-49 mL/min would achieve AUC and C(max) values similar to those observed with 20 mg once daily in patients with normal renal function. The prothrombin time correlated almost linearly with plasma Rivaroxaban concentrations (≤500 μg/L). CONCLUSION: Population analyses of phase II clinical data indicated that the pharmacokinetics and pharmacodynamics of all Rivaroxaban doses were predictable and were affected by expected demographic factors in patients with acute DVT.
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Rivaroxaban population pharmacokinetic analyses in patients treated for acute deep vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention
Clinical Pharmacokinectics, 2011Co-Authors: Wolfgang Mueck, Anthonie W A Lensing, Giancarlo Agnelli, Herve Decousus, Paolo Prandoni, Frank MisselwitzAbstract:Background and objective Rivaroxaban is an oral, direct Factor Xa inhibitor, which is at an advanced stage of clinical development for prevention and treatment of thromboembolic disorders. Two phase II studies, ODIXa-DVT and EINSTEIN DVT, assessed the efficacy and safety of oral Rivaroxaban (once daily or twice daily) for treatment of acute deep-vein thrombosis (DVT). Population pharmacokinetic and pharmacodynamic analyses of Rivaroxaban in patients in these two phase II studies were conducted to characterize the pharmacokinetics/pharmacodynamics of Rivaroxaban and the relationship between important patient covariates and model parameters. Exposure simulations in patients with atrial fibrillation (AF) were also performed in order to predict the exposure of Rivaroxaban, using modified demographic data reflecting the characteristics of a typical AF population. Methods A population pharmacokinetic model was developed using plasma samples from these patients. Various simulations were conducted to explore the pharmacokinetics of Rivaroxaban in patients with DVT and to predict exposure in those with AF. Correlations between plasma Rivaroxaban concentrations and the prothrombin time, Factor Xa activity, HepTest® and activated partial thromboplastin time were also described. Results The pharmacokinetics of Rivaroxaban in patients with DVT were found to be consistent and predictable across all doses studied. The area under the plasma concentration-time curve (AUC) increased dose dependently. The same total daily doses given once daily achieved higher maximum plasma concentration (C(max)) values (∼20%) and lower trough (minimum) plasma concentration (C(trough)) values (∼60%) than when given twice daily; however, the 5th-95th percentile ranges for these parameters overlapped. Rivaroxaban clearance was moderately influenced by age and renal function, and the volume of distribution was influenced by age, body weight and sex; the effects were within the observed interindividual variability. Simulations in virtual patient populations with AF showed that a Rivaroxaban dose of 15 mg once daily in patients with creatinine clearance of 30-49 mL/min would achieve AUC and C(max) values similar to those observed with 20 mg once daily in patients with normal renal function. The prothrombin time correlated almost linearly with plasma Rivaroxaban concentrations (≤500 μg/L). Conclusion Population analyses of phase II clinical data indicated that the pharmacokinetics and pharmacodynamics of all Rivaroxaban doses were predictable and were affected by expected demographic factors in patients with acute DVT.
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population pharmacokinetics and pharmacodynamics of once and twice daily Rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement
Thrombosis and Haemostasis, 2008Co-Authors: Wolfgang Mueck, Frank Misselwitz, Lars C Borris, Ola E Dahl, Sylvia Haas, Menno V Huisman, Ajay K Kakkar, Peter Kalebo, Eva Muelhofer, Bengt I ErikssonAbstract:Rivaroxaban (Xarelto) is an oral, direct factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. The aim was to compare the population pharmacokinetics (PK) and pharmacodynamics (PD) of twice-daily (bid) and once-daily (od) Rivaroxaban in patients undergoing total hip replacement (THR). Blood samples were collected from patients enrolled in two phase IIb, dose-ranging studies undertaken to investigate Rivaroxaban for thromboprophylaxis after THR. A sparse sampling technique was used and the samples were pooled for PK and PD analysis, which used non-linear mixed effect modelling. Rivaroxaban PK (samples from 758 patients) were well described by an oral,one-compartment model; age and renal function influenced clearance, and body surface area affected volume of distribution.When comparing the same total daily doses, maximum plasma concentrations of Rivaroxaban were higher and minimum plasma concentrations were lower with od dosing, compared with bid dosing; however, the 90% intervals overlapped.The area under the plasma concentration–time curve was 18–30% higher in the od than in the bid study. Prothrombin time in seconds (samples from 1181 patients) correlated with Rivaroxaban plasma concentrations in a linear fashion in both studies. In conclusion, the PK and PD of Rivaroxaban were predictable when given either bid or od.These findings, along with the suggested efficacy and safety of Rivaroxaban in the phase II studies, relative to enoxaparin, supported the selection of a convenient, once-daily 10 mg Rivaroxaban dose for investigation in phase III studies.
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dose escalation study of the pharmacokinetics and pharmacodynamics of Rivaroxaban in healthy elderly subjects
Current Medical Research and Opinion, 2008Co-Authors: Dagmar Kubitza, Michael Becka, Angelika Roth, Wolfgang MueckAbstract:ABSTRACTObjective: The aim of this study was to investigate the pharmacokinetics and pharmacodynamics of Rivaroxaban – a novel, oral, direct Factor Xa (FXa) inhibitor – in healthy elderly subjects.Research design and methods: In this single-centre, single-blind, placebo-controlled, parallel-group, dose-escalation study, 48 subjects (aged 60–76 years) were randomized to receive a single oral dose of 30, 40 or 50 mg of Rivaroxaban or placebo.Results: Rivaroxaban was absorbed rapidly, reaching peak plasma concentration (Cmax) 4 h after dosing in all groups. Bioavailability, in terms of the area under the plasma concentration–time curve (AUC) and Cmax, increased slightly (less than dose proportionally) after administration of Rivaroxaban 40 mg compared with 30 mg, but was not increased further with Rivaroxaban 50 mg. Rivaroxaban pharmacodynamic effects (inhibition of FXa activity and prolongation of prothrombin time, activated partial thromboplastin time and HepTest) all showed a similar pattern, with maximum...
Peter Kalebo - One of the best experts on this subject based on the ideXlab platform.
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population pharmacokinetics and pharmacodynamics of once and twice daily Rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement
Thrombosis and Haemostasis, 2008Co-Authors: Wolfgang Mueck, Frank Misselwitz, Lars C Borris, Ola E Dahl, Sylvia Haas, Menno V Huisman, Ajay K Kakkar, Peter Kalebo, Eva Muelhofer, Bengt I ErikssonAbstract:Rivaroxaban (Xarelto) is an oral, direct factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. The aim was to compare the population pharmacokinetics (PK) and pharmacodynamics (PD) of twice-daily (bid) and once-daily (od) Rivaroxaban in patients undergoing total hip replacement (THR). Blood samples were collected from patients enrolled in two phase IIb, dose-ranging studies undertaken to investigate Rivaroxaban for thromboprophylaxis after THR. A sparse sampling technique was used and the samples were pooled for PK and PD analysis, which used non-linear mixed effect modelling. Rivaroxaban PK (samples from 758 patients) were well described by an oral,one-compartment model; age and renal function influenced clearance, and body surface area affected volume of distribution.When comparing the same total daily doses, maximum plasma concentrations of Rivaroxaban were higher and minimum plasma concentrations were lower with od dosing, compared with bid dosing; however, the 90% intervals overlapped.The area under the plasma concentration–time curve was 18–30% higher in the od than in the bid study. Prothrombin time in seconds (samples from 1181 patients) correlated with Rivaroxaban plasma concentrations in a linear fashion in both studies. In conclusion, the PK and PD of Rivaroxaban were predictable when given either bid or od.These findings, along with the suggested efficacy and safety of Rivaroxaban in the phase II studies, relative to enoxaparin, supported the selection of a convenient, once-daily 10 mg Rivaroxaban dose for investigation in phase III studies.
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dose escalation study of Rivaroxaban bay 59 7939 an oral direct factor xa inhibitor for the prevention of venous thromboembolism in patients undergoing total hip replacement
Thrombosis Research, 2007Co-Authors: Bengt I Eriksson, Frank Misselwitz, Lars C Borris, Ola E Dahl, Sylvia Haas, Menno V Huisman, Ajay K Kakkar, Eva Muehlhofer, Peter KaleboAbstract:Abstract Introduction Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in clinical development for the prevention of thromboembolic disorders. The aim of this study was to demonstrate proof-of-principle for Rivaroxaban. Materials and methods This was an open-label, dose-escalation study to assess the efficacy and safety of Rivaroxaban, relative to enoxaparin, for the prevention of venous thromboembolism (VTE) after total hip replacement surgery. Patients were randomized in a 3:1 ratio to Rivaroxaban (2.5, 5, 10, 20 and 30 mg twice daily [bid] or 30 mg once daily [od] starting 6–8 h after surgery) or enoxaparin (40 mg od starting the evening before surgery). Therapy continued until mandatory bilateral venography was performed 5–9 days after surgery. Results A total of 625 patients received therapy, of whom 466 patients were eligible for the per-protocol efficacy analysis. The primary efficacy endpoint – deep vein thrombosis (DVT), pulmonary embolism (PE) or all-cause mortality – occurred in 22.2%, 23.8%, 20.0%, 10.2%, 17.4%, 15.1% and 16.8% of patients receiving Rivaroxaban 2.5, 5, 10, 20, 30 mg bid, 30 mg od and enoxaparin, respectively. The dose-response relationship with Rivaroxaban for the primary efficacy endpoint was not statistically significant ( p = 0.0504), although major VTE (proximal DVT, PE and VTE-related death) decreased dose dependently with Rivaroxaban ( p = 0.0108). Major, post-operative bleeding increased dose dependently with Rivaroxaban ( p = 0.0008), occurring in 0–10.8% of patients, compared with 0% in patients receiving enoxaparin. Conclusions This study demonstrated proof-of-principle for Rivaroxaban for the prevention of VTE after total hip replacement surgery.
Frank Misselwitz - One of the best experts on this subject based on the ideXlab platform.
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erratum to Rivaroxaban population pharmacokinetic analyses in patients treated for acute deep vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention
Clinical Pharmacokinectics, 2011Co-Authors: Wolfgang Mueck, Anthonie W A Lensing, Giancarlo Agnelli, Herve Decousus, Paolo Prandoni, Frank MisselwitzAbstract:BACKGROUND AND OBJECTIVE: Rivaroxaban is an oral, direct Factor Xa inhibitor, which is at an advanced stage of clinical development for prevention and treatment of thromboembolic disorders. Two phase II studies, ODIXa-DVT and EINSTEIN DVT, assessed the efficacy and safety of oral Rivaroxaban (once daily or twice daily) for treatment of acute deep-vein thrombosis (DVT). Population pharmacokinetic and pharmacodynamic analyses of Rivaroxaban in patients in these two phase II studies were conducted to characterize the pharmacokinetics/pharmacodynamics of Rivaroxaban and the relationship between important patient covariates and model parameters. Exposure simulations in patients with atrial fibrillation (AF) were also performed in order to predict the exposure of Rivaroxaban, using modified demographic data reflecting the characteristics of a typical AF population. METHODS: A population pharmacokinetic model was developed using plasma samples from these patients. Various simulations were conducted to explore the pharmacokinetics of Rivaroxaban in patients with DVT and to predict exposure in those with AF. Correlations between plasma Rivaroxaban concentrations and the prothrombin time, Factor Xa activity, HepTest® and activated partial thromboplastin time were also described. RESULTS: The pharmacokinetics of Rivaroxaban in patients with DVT were found to be consistent and predictable across all doses studied. The area under the plasma concentration-time curve (AUC) increased dose dependently. The same total daily doses given once daily achieved higher maximum plasma concentration (C(max)) values (∼20%) and lower trough (minimum) plasma concentration (C(trough)) values (∼60%) than when given twice daily; however, the 5th-95th percentile ranges for these parameters overlapped. Rivaroxaban clearance was moderately influenced by age and renal function, and the volume of distribution was influenced by age, body weight and sex; the effects were within the observed interindividual variability. Simulations in virtual patient populations with AF showed that a Rivaroxaban dose of 15 mg once daily in patients with creatinine clearance of 30-49 mL/min would achieve AUC and C(max) values similar to those observed with 20 mg once daily in patients with normal renal function. The prothrombin time correlated almost linearly with plasma Rivaroxaban concentrations (≤500 μg/L). CONCLUSION: Population analyses of phase II clinical data indicated that the pharmacokinetics and pharmacodynamics of all Rivaroxaban doses were predictable and were affected by expected demographic factors in patients with acute DVT.
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Rivaroxaban population pharmacokinetic analyses in patients treated for acute deep vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention
Clinical Pharmacokinectics, 2011Co-Authors: Wolfgang Mueck, Anthonie W A Lensing, Giancarlo Agnelli, Herve Decousus, Paolo Prandoni, Frank MisselwitzAbstract:Background and objective Rivaroxaban is an oral, direct Factor Xa inhibitor, which is at an advanced stage of clinical development for prevention and treatment of thromboembolic disorders. Two phase II studies, ODIXa-DVT and EINSTEIN DVT, assessed the efficacy and safety of oral Rivaroxaban (once daily or twice daily) for treatment of acute deep-vein thrombosis (DVT). Population pharmacokinetic and pharmacodynamic analyses of Rivaroxaban in patients in these two phase II studies were conducted to characterize the pharmacokinetics/pharmacodynamics of Rivaroxaban and the relationship between important patient covariates and model parameters. Exposure simulations in patients with atrial fibrillation (AF) were also performed in order to predict the exposure of Rivaroxaban, using modified demographic data reflecting the characteristics of a typical AF population. Methods A population pharmacokinetic model was developed using plasma samples from these patients. Various simulations were conducted to explore the pharmacokinetics of Rivaroxaban in patients with DVT and to predict exposure in those with AF. Correlations between plasma Rivaroxaban concentrations and the prothrombin time, Factor Xa activity, HepTest® and activated partial thromboplastin time were also described. Results The pharmacokinetics of Rivaroxaban in patients with DVT were found to be consistent and predictable across all doses studied. The area under the plasma concentration-time curve (AUC) increased dose dependently. The same total daily doses given once daily achieved higher maximum plasma concentration (C(max)) values (∼20%) and lower trough (minimum) plasma concentration (C(trough)) values (∼60%) than when given twice daily; however, the 5th-95th percentile ranges for these parameters overlapped. Rivaroxaban clearance was moderately influenced by age and renal function, and the volume of distribution was influenced by age, body weight and sex; the effects were within the observed interindividual variability. Simulations in virtual patient populations with AF showed that a Rivaroxaban dose of 15 mg once daily in patients with creatinine clearance of 30-49 mL/min would achieve AUC and C(max) values similar to those observed with 20 mg once daily in patients with normal renal function. The prothrombin time correlated almost linearly with plasma Rivaroxaban concentrations (≤500 μg/L). Conclusion Population analyses of phase II clinical data indicated that the pharmacokinetics and pharmacodynamics of all Rivaroxaban doses were predictable and were affected by expected demographic factors in patients with acute DVT.
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population pharmacokinetics and pharmacodynamics of once and twice daily Rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement
Thrombosis and Haemostasis, 2008Co-Authors: Wolfgang Mueck, Frank Misselwitz, Lars C Borris, Ola E Dahl, Sylvia Haas, Menno V Huisman, Ajay K Kakkar, Peter Kalebo, Eva Muelhofer, Bengt I ErikssonAbstract:Rivaroxaban (Xarelto) is an oral, direct factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. The aim was to compare the population pharmacokinetics (PK) and pharmacodynamics (PD) of twice-daily (bid) and once-daily (od) Rivaroxaban in patients undergoing total hip replacement (THR). Blood samples were collected from patients enrolled in two phase IIb, dose-ranging studies undertaken to investigate Rivaroxaban for thromboprophylaxis after THR. A sparse sampling technique was used and the samples were pooled for PK and PD analysis, which used non-linear mixed effect modelling. Rivaroxaban PK (samples from 758 patients) were well described by an oral,one-compartment model; age and renal function influenced clearance, and body surface area affected volume of distribution.When comparing the same total daily doses, maximum plasma concentrations of Rivaroxaban were higher and minimum plasma concentrations were lower with od dosing, compared with bid dosing; however, the 90% intervals overlapped.The area under the plasma concentration–time curve was 18–30% higher in the od than in the bid study. Prothrombin time in seconds (samples from 1181 patients) correlated with Rivaroxaban plasma concentrations in a linear fashion in both studies. In conclusion, the PK and PD of Rivaroxaban were predictable when given either bid or od.These findings, along with the suggested efficacy and safety of Rivaroxaban in the phase II studies, relative to enoxaparin, supported the selection of a convenient, once-daily 10 mg Rivaroxaban dose for investigation in phase III studies.
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effects of the oral direct factor xa inhibitor Rivaroxaban on platelet induced thrombin generation and prothrombinase activity1
The Journal of Clinical Pharmacology, 2007Co-Authors: Jochen Graff, Dagmar Kubitza, Michael Becka, Frank Misselwitz, Nils Von Hentig, Hansklaus Breddin, Sebastian HarderAbstract:Rivaroxaban (BAY 59-7939) is an oral, direct factor Xa inhibitor in advanced development. This study was undertaken to investigate its effects on thrombin generation. In this placebo-controlled, randomized, crossover study, 12 healthy subjects received Rivaroxaban (single 5- or 30-mg dose) or placebo. Thrombin generation was investigated by measuring the endogenous thrombin potential and prothrombinase-induced clotting time. Maximal effect of Rivaroxaban was observed 2 hours after drug administration: prothrombinase-induced clotting time was prolonged 1.8 and 2.3 times baseline after Rivaroxaban 5 and 30 mg, respectively. Collagen-induced endogenous thrombin potential was reduced by approximately 80% and approximately 90% compared with baseline after Rivaroxaban 5 and 30 mg, respectively, and tissue factor-induced endogenous thrombin potential was reduced by approximately 40% (5 mg) and approximately 65% (30 mg), respectively. Thrombin generation remained inhibited for 24 hours. There was a close correlation between plasma concentration of Rivaroxaban and prolongation of prothrombinase-induced clotting time and reduction in endogenous thrombin potential. Rivaroxaban strongly inhibits platelet-induced thrombin generation, after activation of either platelets or the coagulation pathway, even in the presence of minimal factor Xa inhibition in plasma.
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dose escalation study of Rivaroxaban bay 59 7939 an oral direct factor xa inhibitor for the prevention of venous thromboembolism in patients undergoing total hip replacement
Thrombosis Research, 2007Co-Authors: Bengt I Eriksson, Frank Misselwitz, Lars C Borris, Ola E Dahl, Sylvia Haas, Menno V Huisman, Ajay K Kakkar, Eva Muehlhofer, Peter KaleboAbstract:Abstract Introduction Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in clinical development for the prevention of thromboembolic disorders. The aim of this study was to demonstrate proof-of-principle for Rivaroxaban. Materials and methods This was an open-label, dose-escalation study to assess the efficacy and safety of Rivaroxaban, relative to enoxaparin, for the prevention of venous thromboembolism (VTE) after total hip replacement surgery. Patients were randomized in a 3:1 ratio to Rivaroxaban (2.5, 5, 10, 20 and 30 mg twice daily [bid] or 30 mg once daily [od] starting 6–8 h after surgery) or enoxaparin (40 mg od starting the evening before surgery). Therapy continued until mandatory bilateral venography was performed 5–9 days after surgery. Results A total of 625 patients received therapy, of whom 466 patients were eligible for the per-protocol efficacy analysis. The primary efficacy endpoint – deep vein thrombosis (DVT), pulmonary embolism (PE) or all-cause mortality – occurred in 22.2%, 23.8%, 20.0%, 10.2%, 17.4%, 15.1% and 16.8% of patients receiving Rivaroxaban 2.5, 5, 10, 20, 30 mg bid, 30 mg od and enoxaparin, respectively. The dose-response relationship with Rivaroxaban for the primary efficacy endpoint was not statistically significant ( p = 0.0504), although major VTE (proximal DVT, PE and VTE-related death) decreased dose dependently with Rivaroxaban ( p = 0.0108). Major, post-operative bleeding increased dose dependently with Rivaroxaban ( p = 0.0008), occurring in 0–10.8% of patients, compared with 0% in patients receiving enoxaparin. Conclusions This study demonstrated proof-of-principle for Rivaroxaban for the prevention of VTE after total hip replacement surgery.
Elisabeth Perzborn - One of the best experts on this subject based on the ideXlab platform.
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The discovery of Rivaroxaban: translating preclinical assessments into clinical practice
Frontiers in pharmacology, 2013Co-Authors: Dagmar Kubitza, Elisabeth Perzborn, Scott D BerkowitzAbstract:Direct oral anticoagulants that target a single coagulation factor (such as factor Xa or thrombin) have been developed in recent years in an attempt to address some of the limitations of traditional anticoagulants. Rivaroxaban is an oral, direct factor Xa inhibitor that inhibits free and clot-bound factor Xa and factor Xa in the prothrombinase complex. Preclinical studies demonstrated a potent anticoagulant effect of Rivaroxaban in plasma as well as the ability of this agent to prevent and treat venous and arterial thrombosis in animal models. These studies led to an extensive phase I clinical development program that investigated the pharmacological properties of Rivaroxaban in humans. In these studies, Rivaroxaban was shown to exhibit predictable pharmacokinetics and pharmacodynamics and to have no clinically relevant interactions with many commonly prescribed co medications. The pharmacodynamic effects of Rivaroxaban (for example, inhibition of factor Xa and prolongation of prothrombin time) were closely correlated with Rivaroxaban concentrations in plasma. The encouraging findings from preclinical and early clinical studies were expanded upon in large, randomized phase III studies, which demonstrated the clinical efficacy and safety of Rivaroxaban in a broad spectrum of patients. This article provides an overview of the discovery and development of Rivaroxaban, describing the pharmacodynamic profile established in preclinical studies and the optimal translation to clinical studies in healthy subjects and patient populations.
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Reversal of Rivaroxaban anticoagulation by haemostatic agents in rats and primates
Thrombosis and haemostasis, 2013Co-Authors: Elisabeth Perzborn, Ulf Buetehorn, Andras Gruber, Hanna Tinel, Ulla M. Marzec, Buchmüller Anja, Stefan Heitmeier, Volker LauxAbstract:Rivaroxaban is an oral, direct factor Xa inhibitor for the management of thromboembolic disorders. Despite its short half-life, the ability to reverse Rivaroxaban anticoagulation could be beneficial in life-threatening emergencies. The potential of prothrombin complex concentrate (PCC; Beriplex®), activated PCC (aPCC; FEIBA®) or recombinant activated factor VII (rFVIIa; NovoSeven®) to reverse Rivaroxaban in rats and baboons was investigated. Anaesthetised rats pre-treated with intravenous Rivaroxaban (2 mg/kg) received intravenous rFVIIa (100/400 μg/kg), PCC (25/50 U/kg) or aPCC (50/100 U/kg) after initiation of bleeding. Clotting times and bleeding times (BTs) were recorded. Rivaroxaban was administered as an intravenous 0.6 mg/kg bolus followed by continuous 0.6 mg/kg/hour infusion in baboons. Animals received intravenous aPCC 50 U/kg (2 U/kg/minute) or rFVIIa 210 μg/kg. BT and clotting parameters were measured. In rats pretreated with high-dose Rivaroxaban, PCC 50 U/kg, aPCC 100 U/kg and rFVIIa 400 μg/kg significantly reduced BT vs Rivaroxaban alone (5.4 ± 1.4-fold to 1.5 ± 0.4-fold [p
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accurate determination of Rivaroxaban levels requires different calibrator sets but not addition of antithrombin
Thrombosis and Haemostasis, 2012Co-Authors: Helen Mani, Gabriele Rohde, Gertrud Stratmann, Christian Hesse, Natalie Herth, Stephan Schwers, Elisabeth Perzborn, Edelgard LindhofflastAbstract:Rivaroxaban is a direct factor Xa inhibitor, which can be monitored by anti-factor Xa chromogenic assays. This ex vivo study evaluated different assays for accurate determination of Rivaroxaban levels. Eighty plasma samples from patients receiving Rivaroxaban (Xarelto) 10 mg once daily and 20 plasma samples from healthy volunteers were investigated using one anti-factor Xa assay with the addition of exogenous antithrombin and two assays without the addition of antithrombin. Two different lyophilised Rivaroxaban calibration sets were used for each assay (low concentration set: 0, 14.5, 59.6 and 97.1 ng/ml; high concentration set: 0, 48.3, 101.3, 194.2 and 433.3 ng/ml). Using a blinded study design, the Rivaroxaban concentrations determined by the assays were compared with concentrations measured by HPLC-MS/MS. All assays showed a linear relationship between the Rivaroxaban concentrations measured by HPLC-MS/MS and the optical density of the anti-FXa assays. However, the assay with the addition of exogenous antithrombin detected falsely high concentrations of Rivaroxaban even in plasma samples from controls who had not taken Rivaroxaban (intercept values using the high calibrator set and the low calibrator set: +26.49 ng/ml and +13.71 ng/ml, respectively). Plasma samples, initially determined by the high calibrator setting and containing Rivaroxaban concentrations <25 ng/ml, had to be re-run using the low calibrator setting for precise measurement. In conclusion, anti-factor Xa chromogenic assays that use Rivaroxaban calibrators at different concentration levels can be used to measure accurately a wide range of Rivaroxaban concentrations ex vivo. Assays including exogenous antithrombin are unsuitable for measurement of Rivaroxaban.
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evaluation of the prothrombin time for measuring Rivaroxaban plasma concentrations using calibrators and controls results of a multicenter field trial
Clinical and Applied Thrombosis-Hemostasis, 2012Co-Authors: Meyer Michel Samama, Elisabeth Perzborn, Céline Guinet, Genevieve Contant, Theodore E Spiro, Yves Gourmelin, Lena Le Flem, Jean-luc MartinoliAbstract:This study evaluated the prothrombin time (PT) assay for the measurement of plasma concentrations of Rivaroxaban using calibrators and controls. The intra- and interlaboratory precision of the measurement was investigated in a field trial involving 21 laboratories. Each laboratory was provided with Rivaroxaban calibrators and control plasma samples containing different concentrations of Rivaroxaban, and PT reagents. The evaluation was carried out over 2 consecutive weeks using centrally provided and local PT reagents. A calibration curve was produced each day (for inter-run precision), and day-to-day precision was evaluated by testing 3 control plasma samples. A large interlaboratory variation (in seconds) was observed with local PT reagents. The results were less variable when expressed as Rivaroxaban concentrations (ng/mL) or when central PT reagent was used (STA Neoplastine CI Plus). The widely available PT assay, in conjunction with Rivaroxaban calibrators, may be useful for the measurement of peak plasma levels of Rivaroxaban.
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evaluation of the anti factor xa chromogenic assay for the measurement of Rivaroxaban plasma concentrations using calibrators and controls
Thrombosis and Haemostasis, 2011Co-Authors: Meyer Michel Samama, Gabriele Rohde, Elisabeth Perzborn, Céline Guinet, Genevieve Contant, Theodore E Spiro, Yves Gourmelin, Lena Le Flem, Jean-luc MartinoliAbstract:Rivaroxaban is an oral, direct factor Xa inhibitor. Routine coagulation monitoring is not required, but a quantitative determination of Rivaroxaban concentrations might be useful in some clinical circumstances. This multicentre study assessed the suitability of the anti-factor Xa chromogenic assay for the measurement of Rivaroxaban plasma concentrations (ng/ml) using Rivaroxaban calibrators and controls, and the inter-laboratory precision of the measurement. Twenty-four centres in Europe and North America were provided with sets of Rivaroxaban calibrators (0, 41, 209 and 422 ng/ml) and a set of Rivaroxaban pooled human plasma controls (20, 199 and 662 ng/ml; the concentrations were unknown to the participating laboratories). The evaluation was carried out over 10 days by each laboratory using local anti-factor Xa reagents as well as the centrally provided reagent, a modified STA® Rotachrom® assay. A calibration curve was produced each day, and the day-to-day precision was evaluated by testing three human plasma controls. When using the local anti-factor Xa reagents, the mean Rivaroxaban concentrations (measured/actual values) were: 17/20, 205/199 and 668/662 ng/ml, and the coefficient of variance (CV) was 37.0%, 13.7% and 14.1%, respectively. When the modified STA Rotachrom method was used, the measured/actual values were: 18/20, 199/199 and 656/662 ng/ml, and the CV was 19.1%, 10.9% and 10.0%, respectively. The results suggest that, by using Rivaroxaban calibrators and controls, the anti-factor Xa chromogenic method is suitable for measuring a wide range of Rivaroxaban plasma concentrations (20-660 ng/ml), which covers the expected Rivaroxaban plasma levels after therapeutic doses.
