Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor

Kubitza, Dagmar; Becka, Michael; Voith, Barbara; Zuehlsdorf, Michael; Wensing, Georg

doi:10.1016/j.clpt.2005.06.011

Cited by 593 publications

(652 citation statements)

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“…A semi-PBPK model was chosen for rivaroxaban because its human pharmacokinetic profile exhibits an apparent one compartmental distribution behavior [11]. In contrast to a 'full' PBPK model in which organs and tissues are separately represented, a 'semi' PBPK model combines tissues having similar drug partitioning and distribution equilibrium with the plasma compartment [12].…”

Section: General Pbpk Model Buildingmentioning

confidence: 99%

“…The PBPK model was customized to incorporate drug-dependent parameters estimated from human plasma pharmacokinetic studies [11], including the first order absorption rate constant (K a ) describing drug transfer from the gut compartment to the portal vein compartment, V ss , and CL comprising hepatic and renal contributions (CL H and CL R ) as outlined in Table 1. Geometric mean plasma rivaroxaban concentration versus time data from the literature [11] were digitized (GetData software, Version 2.24, Digital River Inc., Cologne, Germany).…”

Section: Rivaroxaban Pbpk Modelmentioning

confidence: 99%

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Utility of a physiologically–based pharmacokinetic (PBPK) modeling approach to quantitatively predict a complex drug–drug–disease interaction scenario for rivaroxaban during the drug review process: implications for clinical practice

Grillo

Zhao

Bullock

et al. 2012

Biopharm & Drug Disp

102

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Background: Rivaroxaban is an oral Factor Xa inhibitor. The primary objective of this communication was to quantitatively predict changes in rivaroxaban exposure when individuals with varying degrees of renal impairment are co-administered with another drug that is both a P-gp and a moderate CYP3A4 inhibitor. Methods: A physiologically based pharmacokinetic (PBPK) model was developed to simulate rivaroxaban pharmacokinetics in young (20-45 years) or older (55-65 years) subjects with normal renal function, mild, moderate and severe renal impairment, with or without concomitant use of the combined P-gp and moderate CYP3A4 inhibitor, erythromycin. Results: The simulations indicate that combined factors (i.e., renal impairment and the use of erythromycin) have a greater impact on rivaroxaban exposure than expected when the impact of these factors are considered individually. Compared with normal young subjects taking rivaroxaban, concurrent mild, moderate or severe renal impairment plus erythromycin resulted in 1.9-, 2.4-or 2.6-fold increase in exposure, respectively in young subjects; and 2.5-, 2.9-or 3.0-fold increase in exposure in older subjects. Conclusions: These simulations suggest that a drug-drug-disease interaction is possible, which may significantly increase rivaroxaban exposure and increase bleeding risk. These simulations render more mechanistic insights as to the possible outcomes and allow one to reach a decision to add cautionary language to the approved product labeling for rivaroxaban. Copyright © 2012 John Wiley & Sons, Ltd.

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Section: General Pbpk Model Buildingmentioning

confidence: 99%

Section: Rivaroxaban Pbpk Modelmentioning

confidence: 99%

Utility of a physiologically–based pharmacokinetic (PBPK) modeling approach to quantitatively predict a complex drug–drug–disease interaction scenario for rivaroxaban during the drug review process: implications for clinical practice

Grillo

Zhao

Bullock

et al. 2012

Biopharm & Drug Disp

102

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“…Rivaroxaban is contraindicated in patients whose creatinine clearance rate is less than 15 mL/min. 48–52 …”

Section: Clinical Risk Factors For Strokementioning

confidence: 99%

Selecting antithrombotic therapy for patients with atrial fibrillation

Tanaka-Esposito

Chung

2015

CCJM

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When considering anticoagulant therapy for patients with atrial fibrillation, one must balance the reduction in risk of thromboembolism that this therapy offers against the risk of bleeding that it poses. The American Heart Association, American College of Cardiology, and Heart Rhythm Society updated their atrial fibrillation guidelines in 2014. This review outlines a rationale for clinical decision-making based on the new guidelines and summarizes the currently approved drugs.

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“…Rivaroxaban is an oral factor Xa inhibitor that has a peak anticoagulant effect within 2 to 4 hours after dosing and predictable pharmacokinetic and pharmacodynamic properties that obviate the need for routine anticoagulation laboratory monitoring 1, 2. Rivaroxaban has been shown to be associated with a dose‐dependent inhibition of factor Xa activity across all doses investigated,1, 2, 3, 4 and maximum inhibition did not vary significantly between initial and steady‐state administration 2.…”

mentioning

confidence: 99%

“…Rivaroxaban has been shown to be associated with a dose‐dependent inhibition of factor Xa activity across all doses investigated,1, 2, 3, 4 and maximum inhibition did not vary significantly between initial and steady‐state administration 2. The onset of action of rivaroxaban is as rapid as that of low‐molecular‐weight heparins (LMWHs) 5.…”

mentioning

confidence: 99%

Use of Prestudy Heparin Did Not Influence the Efficacy and Safety of Rivaroxaban in Patients Treated for Symptomatic Venous Thromboem‐bolism in the EINSTEIN DVT and EINSTEIN PE Studies

Prandoni

Prins

Cohen

et al. 2015

Academic Emergency Medicine

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ObjectivesIn the EINSTEIN DVT and EINSTEIN PE studies, the majority of patients received heparins to bridge the period during venous thromboembolism (VTE) diagnosis confirmation and the start of the study. In contrast to vitamin K antagonists (VKAs), rivaroxaban may not require initial heparin treatment.MethodsTo evaluate the effect of prestudy heparin on the efficacy and safety of rivaroxaban relative to enoxaparin/VKA, the 3‐month incidence of recurrent VTE, and the 14‐day incidence of major and nonmajor clinically relevant bleeding were compared in patients who did and did not receive prestudy heparin.ResultsOf the 8,281 patients randomized, 6,937 (83.8%) received prestudy heparin (mean ± SD duration = rivaroxaban: 1.04 [± 0.74] days; enoxaparin 1.03 [± 0.42] days), and 1,344 (16.2%) did not. In patients who did not receive prestudy heparin, the incidences of recurrent VTE were similar in rivaroxaban (15 of 649, 2.3%) and enoxaparin/VKA (13 of 695, 1.9%) patients (adjusted hazard ratio [HR] = 1.11; 95% confidence interval [CI] = 0.52 to 2.37). The incidences of recurrent VTE were also similar in rivaroxaban (54 of 3,501, 1.5%) and enoxaparin/VKA (69 of 3,436, 2.0%) patients who did receive prestudy heparin (adjusted HR = 0.74; 95% CI = 0.52 to 1.06; pinteraction = 0.32). The incidences of major or nonmajor clinically relevant bleeding with rivaroxaban were not significantly different from those with enoxaparin/VKA, either with (105 of 3,485, 3.0% vs. 104 of 3,428, 3.0%; adjusted HR = 0.98; 95% CI = 0.75 to 1.29) or without (24 of 645, 3.7% vs. 30 of 688, 4.4%; adjusted HR = 0.81; 95% CI = 0.46 to 1.40; pinteraction = 0.68) prestudy heparin.ConclusionsAlthough the majority of patients in the EINSTEIN studies received prestudy heparin, there were no notable differences in treatment effect of rivaroxaban versus enoxaparin/VKA in those who did and did not receive it.

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Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor

Abstract: BAY 59--7939 was well tolerated with predictable pharmacodynamics and pharmacokinetics across a wide range of doses in healthy male subjects. BAY 59--7939 was shown to be an effective and specific factor Xa inhibitor.

Cited by 593 publications

References 31 publications

Utility of a physiologically–based pharmacokinetic (PBPK) modeling approach to quantitatively predict a complex drug–drug–disease interaction scenario for rivaroxaban during the drug review process: implications for clinical practice

Utility of a physiologically–based pharmacokinetic (PBPK) modeling approach to quantitatively predict a complex drug–drug–disease interaction scenario for rivaroxaban during the drug review process: implications for clinical practice

Selecting antithrombotic therapy for patients with atrial fibrillation

Use of Prestudy Heparin Did Not Influence the Efficacy and Safety of Rivaroxaban in Patients Treated for Symptomatic Venous Thromboem‐bolism in the EINSTEIN DVT and EINSTEIN PE Studies

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