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Background: Four-factor prothrombin complex concentrates (PCCs), which contain factor II, FVII, FIX, and FX, have shown the potential to reverse the anticoagulant effect of rivaroxaban in healthy volunteers. The purpose of this study was to determine whether a three-factor PCC, which contains little FVII, has a similar effect., Methods and Results: We performed an open-label, single-center, parallel-group study comparing the effect of a three-factor PCC (Profilnine SD) with that of a four-factor PCC (Beriplex P/N) on the pharmacodynamics of rivaroxaban in 35 healthy volunteers. After receiving 4 days of rivaroxaban 20 mg twice daily to obtain supratherapeutic steady-state concentrations, volunteers were randomized to receive a single 50 IU kg(-1) bolus dose of four-factor PCC, three-factor PCC or saline 4 h after the morning dose of rivaroxaban on day 5, and the effects of these interventions on prothrombin time and thrombin generation were determined. Within 30 min, four-factor PCC reduced mean prothrombin time by 2.5-3.5 s, whereas three-factor PCC produced only a 0.6-1.0-s reduction. In contrast, three-factor PCC reversed rivaroxaban-induced changes in thrombin generation more than four-factor PCC., Conclusions: This study demonstrates the potential of both three-factor and four-factor PCCs to at least partially reverse the anticoagulant effects of rivaroxaban in healthy adults. The discrepant effects of the PCC preparations may reflect differences in the procoagulant components present in each., (© 2014 International Society on Thrombosis and Haemostasis.)

Aims: This study investigated relevant pharmacodynamic and pharmacokinetic parameters during the transition from warfarin to rivaroxaban in healthy male subjects., Methods: Ninety-six healthy men were randomized into the following three groups: warfarin [international normalized ratio (INR) 2.0-3.0] transitioned to rivaroxaban 20 mg once daily (od; group A); warfarin (INR 2.0-3.0) followed by placebo od (group B); and rivaroxaban alone 20 mg od (group C) for 4 days. Anti-factor Xa activity, inhibition of factor Xa activity, prothrombin time (PT), activated partial thromboplastin time, HepTest, prothrombinase-induced clotting time, factor VIIa activity, factor IIa activity, endogenous thrombin potential and pharmacokinetics were measured., Results: An additive effect was observed on the PT and PT/INR during the initial transition period. The mean maximal prolongation of PT was 4.39-fold [coefficient of variation (CV) 18.03%; range 3.39-6.50] of the baseline value in group A, compared with 1.88-fold (CV 10.35%; range 1.53-2.21) in group B and 1.57-fold (CV 9.98%; range 1.37-2.09) in group C. Rivaroxaban had minimal influence on the PT/INR at trough levels. Inhibition of factor Xa activity, activated partial thromboplastin time and endogenous thrombin potential were also enhanced, but to a lesser extent. In contrast, the effects of rivaroxaban on anti-factor Xa activity, HepTest and prothrombinase-induced clotting time were not affected by pretreatment with warfarin., Conclusions: Changes in pharmacodynamics during the transition from warfarin to rivaroxaban vary depending on the test used. A supra-additive effect on PT/INR is expected during the initial period of transition, but pretreatment with warfarin does not influence the effect of rivaroxaban on anti-factor Xa activity., (© 2014 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)

The use of anticoagulants in neonates is increasing because of the medical advances improving the long-term survival of very sick infants who are at risk of venous thromboembolism (VTE). Current anticoagulation therapy in neonates is less than ideal, because of the physiological differences compared to children and adults regarding the pathophysiology of thrombosis and pharmacology of the drug. Limitations associated with conventional anticoagulants have prompted the development of novel drugs that specifically target the key proteins in the coagulation system. Rivaroxaban is the first oral, direct Factor Xa inhibitor available for the prevention of VTE in adults. Its predictable pharmacokinetic profile, high oral bioavailability and once-daily dosing make rivaroxaban an optimal anticoagulant that warrants investigation in neonates. This study was designed to determine whether there are age-related differences in the pharmacodynamic effects of rivaroxaban in vitro amongst neonates. Neonatal and adult plasma pools were created and spiked with increasing concentrations of rivaroxaban (0-500 ng/ml). Commercially available prothrombin time (PT), activated partial thromboplastin time (aPTT) and anti-Factor Xa assays as well as a sub-sampling thrombin generation assay were used to measure the rivaroxaban effect. A dose-dependent response was observed for PT, aPTT and lag time in both the age groups. Rivaroxaban caused a significant increase in the clotting time for PT and aPTT as well as an increase in lag time (as measured by thrombin generation) in neonates when compared with adults. In-vivo studies are required to confirm the consistency of dose-response in neonates.

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.

Aims: The anticoagulant rivaroxaban is an oral, direct Factor Xa inhibitor for the management of thromboembolic disorders. Metabolism and excretion involve cytochrome P450 3A4 (CYP3A4) and 2J2 (CYP2J2), CYP-independent mechanisms, and P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) (ABCG2)., Methods: The pharmacokinetic effects of substrates or inhibitors of CYP3A4, P-gp and Bcrp (ABCG2) on rivaroxaban were studied in healthy volunteers., Results: Rivaroxaban did not interact with midazolam (CYP3A4 probe substrate). Exposure to rivaroxaban when co-administered with midazolam was slightly decreased by 11% (95% confidence interval [CI] -28%, 7%) compared with rivaroxaban alone. The following drugs moderately affected rivaroxaban exposure, but not to a clinically relevant extent: erythromycin (moderate CYP3A4/P-gp inhibitor; 34% increase [95% CI 23%, 46%]), clarithromycin (strong CYP3A4/moderate P-gp inhibitor; 54% increase [95% CI 44%, 64%]) and fluconazole (moderate CYP3A4, possible Bcrp [ABCG2] inhibitor; 42% increase [95% CI 29%, 56%]). A significant increase in rivaroxaban exposure was demonstrated with the strong CYP3A4, P-gp/Bcrp (ABCG2) inhibitors (and potential CYP2J2 inhibitors) ketoconazole (158% increase [95% CI 136%, 182%] for a 400 mg once daily dose) and ritonavir (153% increase [95% CI 134%, 174%])., Conclusions: Results suggest that rivaroxaban may be co-administered with CYP3A4 and/or P-gp substrates/moderate inhibitors, but not with strong combined CYP3A4, P-gp and Bcrp (ABCG2) inhibitors (mainly comprising azole-antimycotics, apart from fluconazole, and HIV protease inhibitors), which are multi-pathway inhibitors of rivaroxaban clearance and elimination., (© 2013 Bayer Pharma AG. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.)

Introduction: Rivaroxaban, a direct factor Xa inhibitor, has demonstrated effectiveness for the management of both venous and arterial thrombosis. This study was designed to investigate the antithrombotic effect of rivaroxaban, with or without acetylsalicylic acid (ASA), in an ex vivo perfusion chamber at both low and high shear rates., Materials and Methods: Healthy subjects (N=51) were enrolled in a randomized, crossover (rivaroxaban 5, 10 or 20mg with or without ASA), and parallel-group (compared with ASA plus clopidogrel) study. Thrombi formed on pig aorta strips were measured after a 5-minute perfusion at low and high shear rates with blood from the subjects by measuring D-dimer concentration (for fibrin deposition) and P-selectin content (for platelet deposition)., Results: ASA alone had no impact on thrombus D-dimer levels, whereas rivaroxaban alone at peak concentrations decreased D-dimer levels by 9%, 84% and 65% at low shear rate and 37%, 73% and 74% at high shear rate after doses of 5, 10 and 20mg, respectively. Steady-state ASA plus rivaroxaban 5mg caused a greater reduction in D-dimer levels (63%) than monotherapy at low shear rate. Co-administration of ASA with clopidogrel was associated with a 30% decrease in D-dimer levels at low shear rate and a 14% decrease at high shear rate. No conclusive effect on P-selectin content was observed across the treatment groups., Conclusions: Rivaroxaban dose-dependently inhibited ex vivo thrombus formation under low and high shear rates. Co-administration of ASA had an additional effect on the antithrombotic action of low-dose rivaroxaban., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: Doses of 10 mg, 15 mg, and 20 mg of rivaroxaban are approved for the treatment and prevention of thromboembolic disorders in adult patients. In six Phase I studies, the pharmacokinetics, safety, and tolerability of 2.5 mg, 5 mg, 10 mg, 15 mg, and 20 mg rivaroxaban were investigated in healthy male subjects, and the influence of food on these parameters was investigated for the 10 mg, 15 mg, and 20 mg tablet doses. In addition, an oral suspension containing 1 mg/ml rivaroxaban, which is under investigation for future use in the pediatric population, was investigated at doses of 10 mg and 20 mg., Materials: Rivaroxaban was obtained from Bayer Pharma AG, Wuppertal, Germany., Methods: Six independent, single-dose, cross-over studies were performed in healthy male subjects (between 13 and 24 subjects were enrolled in each study) to determine the pharmacokinetics, safety, and tolerability of rivaroxaban under fasting and fed conditions. Study 1 was an absolute bioavailability study that compared 5 mg and 20 mg tablet doses with a 1 mg intravenous solution. Studies 2 and 3 were confirmatory food-effect studies that assessed 10 mg and 20 mg tablet doses, respectively, under fed and fasting conditions. Study 4 was a formulation study that evaluated oral suspensions of 10 mg (fasting) and 20 mg (fasting and fed) rivaroxaban vs. a 10 mg tablet (fasted). Study 5 was a dose-proportionality study that assessed 2.5 mg, 5 mg, and 10 mg tablets under fasting conditions. Study 6 was a dose-proportionality study that assessed tablet doses of 10 mg, 15 mg, and 20 mg under fed conditions. Pharmacokinetic parameters, including the area under the plasma concentration-time curve after a single dose, the maximum drug concentration in plasma after a single dose, dose-adjusted values of area under the plasma concentration-time curve and maximum drug concentration in plasma after a single dose, half-life associated with the terminal slope, and time to maximum concentration in plasma after a single dose were evaluated. Adverse events were classified according to their degree of severity and were summarized using Medical Dictionary for Regulatory Activities preferred terms., Results: At all doses, rivaroxaban showed an acceptable safety profile and was well tolerated in healthy individuals. Independent of food and formulation, pharmacokinetic parameters of doses up to 10 mg rivaroxaban were dose proportional and had high oral bioavailability (≥ 80%). Under fasting conditions, pharmacokinetic parameters of 15 mg and 20 mg rivaroxaban increased with dose but were less than dose proportional. However, when taken with food, high bioavailability (≥ 80%) of these doses was achieved independent of formulation., Conclusion: Pharmacokinetic parameters of doses up to 10 mg rivaroxaban were dose proportional and had high oral bioavailability independent of food or whether administered as tablet or solution. High bioavailability (≥ 80%) of 15 mg and 20 mg rivaroxaban was achieved when taken with food; therefore, these doses need to be taken with food.

The development of rivaroxaban (XARELTO®) is an important new medical advance in the field of oral anticoagulation. Thrombosis-mediated conditions constitute a major burden for patients, healthcare systems, and society. For more than 60 years, the prevention and treatment of these conditions have been dominated by oral vitamin K antagonists (such as warfarin) and the injectable heparins. Thrombosis can lead to several conditions, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and/or death. Prevention and treatment of thrombosis with an effective, convenient-to-use oral anticoagulant with a favorable safety profile is critical, especially in an aging society in which the risk of thrombosis, and the potential for bleeding complications, is increasing. Rivaroxaban acts to prevent and treat thrombosis by potently inhibiting coagulation Factor Xa in the blood. Factor Xa converts prothrombin to thrombin, which initiates the formation of blood clots by converting fibrinogen to clot-forming fibrin and leads to platelet activation. After a large and novel clinical development program in over 75,000 patients to date, rivaroxaban has received approval for multiple indications in the United States, European Union, and other countries worldwide to prevent and treat several thrombosis-mediated conditions. This review will highlight some of the unique aspects of the rivaroxaban development program., (© 2013 New York Academy of Sciences.)

Aim: This study investigated the effects of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban (10 mg), an oral, direct Factor Xa inhibitor., Method: This single centre, non-randomized, non-blinded study included subjects with mild (n = 8) or moderate hepatic impairment (n = 8), according to the Child-Pugh classification, and gender-matched healthy subjects (n = 16)., Results: Rivaroxaban was well tolerated irrespective of hepatic function. Mild hepatic impairment did not significantly affect the pharmacokinetics or pharmacodynamics of rivaroxaban, compared with healthy subjects. However, in subjects with moderate hepatic impairment, total body clearance was decreased, leading to a significant increase in the area under the plasma concentration-time curve (AUC). The least-squares (LS)-mean values for AUC were 1.15-fold [90% confidence interval (CI) 0.85, 1.57] and 2.27-fold (90% CI 1.68, 3.07) higher in subjects with mild and moderate hepatic impairment, respectively, than in healthy subjects. Consequently, the pharmacodynamic responses were significantly enhanced in subjects with moderate hepatic impairment. For inhibition of Factor Xa, increases in the area under the effect-time curve and the maximum effect were observed, with LS-mean ratios of 2.59 and 1.24, respectively, vs. healthy subjects. Prolongation of prothrombin time was similar in healthy subjects and those with mild hepatic impairment, but was significantly enhanced in those with moderate hepatic impairment., Conclusion: Moderate (but not mild) hepatic impairment reduced total body clearance of rivaroxaban after a single 10 mg dose, leading to increased rivaroxaban exposure and pharmacodynamic effects., (© 2013 Bayer Pharma AG. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.)

A randomized, single-blind, placebo-controlled, parallel-group study was conducted to assess the effect of age and gender on the pharmacokinetics and pharmacodynamics of rivaroxaban - an oral, direct Factor Xa inhibitor. Subjects (n = 34) were enrolled into four groups: young males or females (aged 18-45 years) and elderly males or females (aged >75 years), and received a single dose of 10 mg rivaroxaban. Pharmacokinetic and pharmacodynamic parameters were determined. Gender had no significant influence on the pharmacokinetics and pharmacodynamics of rivaroxaban. The area under the concentration-time curve (AUC) of rivaroxaban was 41% higher in elderly compared with young subjects; corresponding AUC values for the inhibition of Factor Xa activity and prolongation of prothrombin time were also higher. These changes were the result of reduced rivaroxaban clearance in elderly subjects, mainly owing to decreased renal function. The influence of age was not considered clinically relevant. The maximum plasma concentration was not increased in elderly subjects, and pharmacodynamic parameters returned close to baseline within 24 hours. The results indicate that age alone and gender did not have a clinically relevant effect on the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy subjects after a 10 mg dose., (© The Author(s) 2013.)

Introduction: Current anticoagulation therapy in children is less than ideal, requiring regular venous monitoring and dosing adjustments. Limitations associated with conventional anticoagulants have prompted the development of novel drugs that specifically target key proteins in the coagulation system. Rivaroxaban is the first oral, direct Factor Xa inhibitor available for the prevention of venous thromboembolism in adults. Its predictable pharmacokinetic profile, high oral bioavailability and once-daily dosing make rivaroxaban an optimal anticoagulant that warrants investigation in children. The aim of this study was to investigate the age-related anticoagulant effect of rivaroxaban in vitro., Materials and Methods: Age-specific plasma pools were created (i.e. 28 days-23 months, 2-6, 7-11, 12-16 years and adults) and spiked with increasing concentrations of rivaroxaban (0-500 ng/ml). Commercially available PT, APTT and anti-Factor Xa assays, as well as sub-sampling thrombin generation assays, were used to measure rivaroxaban effect., Results: The results of this study indicate that there are no significant differences in rivaroxaban effect across the age groups in vitro., Conclusion: In vivo studies are required to confirm the consistency of dose-response across the paediatric age groups., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To investigate potential interactions between rivaroxaban, an oral direct Factor Xa inhibitor approved for the management of thromboembolic disorders, and digoxin or atorvastatin., Methods: Two randomized, phase 1 clinical trials were undertaken in healthy men to assess pharmacokinetic and pharmacodynamic interactions between rivaroxaban and digoxin or atorvastatin, and the safety of these drug combinations., Results: Steady-state rivaroxaban did not affect the pharmacokinetic profile of steady-state digoxin (n = 17). Digoxin did not significantly influence the pharmacokinetic profile of single-dose rivaroxaban and had minimal effects on rivaroxaban-induced inhibition of Factor Xa activity and prolongation of clotting time. Similarly, steady-state atorvastatin did not affect the pharmacokinetic profile or the pharmacodynamics of rivaroxaban and vice versa (n = 19). All drugs (alone or in combination) were well tolerated., Conclusions: There were no clinically relevant pharmacokinetic or pharmacodynamic interactions between rivaroxaban and digoxin, or between rivaroxaban and atorvastatin, suggesting that rivaroxaban can be coadministered with either drug. This study also confirmed that rivaroxaban does not interact with substrates for permeability (P)-glycoprotein alone (digoxin) or P-glycoprotein and cytochrome P(450) (CYP)3A4 (atorvastatin).

The activated serine protease factor Xa is a promising target for new anticoagulants. After studies on naturally occurring factor Xa inhibitors indicated that such agents could be effective and safe, research focused on small-molecule direct inhibitors of factor Xa that might address the major clinical need for improved oral anticoagulants. In 2008, rivaroxaban (Xarelto; Bayer HealthCare) became the first such compound to be approved for clinical use. This article presents the history of rivaroxaban's development, from the structure-activity relationship studies that led to its discovery to the preclinical and clinical studies, and also provides a brief overview of other oral anticoagulants in advanced clinical development.

Aim: This study evaluated the effects of impaired renal function on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban (10mg single dose), an oral, direct Factor Xa inhibitor., Methods: Subjects (n= 32) were stratified based on measured creatinine clearance: healthy controls (≥80ml min(-1) ), mild (50-79mlmin(-1) ), moderate (30-49mlmin(-1) ) and severe impairment (<30mlmin(-1) )., Results: Renal clearance of rivaroxaban decreased with increasing renal impairment. Thus, plasma concentrations increased and area under the plasma concentration-time curve (AUC) LS-mean values were 1.44-fold (90% confidence interval [CI] 1.1, 1.9; mild), 1.52-fold (90% CI 1.2, 2.0; moderate) and 1.64-fold (90% CI 1.2, 2.2; severe impairment) higher than in healthy controls. Corresponding values for the LS-mean of the AUC for prolongation of prothrombin time were 1.33-fold (90% CI 0.92, 1.92; mild), 2.16-fold (90% CI 1.51, 3.10 moderate) and 2.44-fold (90% CI 1.70, 3.49 severe) higher than in healthy subjects, respectively. Likewise, the LS-mean of the AUC for Factor Xa inhibition in subjects with mild renal impairment was 1.50-fold (90% CI 1.07, 2.10) higher than in healthy subjects. In subjects with moderate and severe renal impairment, the increase was 1.86-fold (90% CI 1.34, 2.59) and 2.0-fold (90% CI 1.44, 2.78) higher than in healthy subjects, respectively., Conclusions: Rivaroxaban clearance is decreased with increasing renal impairment, leading to increased plasma exposure and pharmacodynamic effects, as expected for a partially renally excreted drug. However, the influence of renal function on rivaroxaban clearance was moderate, even in subjects with severe renal impairment., (© 2010 The Authors. British Journal of Clinical Pharmacology © 2010 The British Pharmacological Society.)

Rivaroxaban is a direct inhibitor of factor Xa, a coagulation factor at a critical juncture in the blood coagulation pathway leading to thrombin generation and clot formation. It is selective for human factor Xa, for which it has >10 000-fold greater selectivity than for other biologically relevant serine proteases (half-maximal inhibitory concentration [IC(50)], >20 micromol/L). Rivaroxaban inhibits factor Xa in a concentration-dependent manner (inhibitory constant [K(i)], 0.4 nmol/L) and binds rapidly (kinetic association rate constant [k(on)], 1.7x10(7) mol/L(-1) s(-1)) and reversibly (kinetic dissociation rate constant [k(off)], 5x10(-3) s(-1)). By inhibiting prothrombinase complex-bound (IC(50), 2.1 nmol/L) and clot-associated factor Xa (IC(50), 75 nmol/L), rivaroxaban reduces the thrombin burst during the propagation phase. In animal models of venous and arterial thrombosis, rivaroxaban showed dose-dependent antithrombotic activity. In healthy individuals, rivaroxaban was found to have predictable pharmacokinetics and pharmacodynamics across a 5- to 80-mg total daily dose range, inhibiting factor Xa activity and prolonging plasma clotting time. In phase III clinical trials, rivaroxaban regimens reduced rates of venous thromboembolism in patients after total hip or knee arthroplasty compared with enoxaparin regimens, without significant differences in rates of major bleeding, showing that rivaroxaban has a favorable benefit-to-risk profile.

Rivaroxaban is a novel, oral, direct factor Xa (FXa) inhibitor for the prevention and treatment of thromboembolic disorders. The aim of this study was to investigate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in healthy, elderly Chinese subjects. In this single-centre, single-blind, placebo-controlled, parallel-group, dose-escalation study, 79 subjects, aged 59-74years (mean 62.8), were randomised to receive once-daily oral doses of rivaroxaban 5, 10, 20, 30 or 40mg. Rivaroxaban was well tolerated: there was a low incidence of treatment-emergent adverse events and all events were of mild intensity. Rivaroxaban was absorbed rapidly, reaching maximum plasma concentrations within 2-4hours. The PK of rivaroxaban were dose dependent over the dose range tested. Maximal inhibition of FXa occurred 2-3hours after dosing and returned to baseline after 24-48hours, reflecting rivaroxaban plasma concentrations. Inhibition of FXa was associated with dose-dependent effects on global clotting tests. There were no clinically relevant differences in rivaroxaban plasma concentrations between male and female subjects. In conclusion, rivaroxaban was well tolerated and was found to have predictable PK and PD in healthy, elderly Chinese subjects.

Aims: To investigate the safety, pharmacokinetics and pharmacodynamics of rivaroxaban, an oral, direct Factor Xa (FXa) inhibitor, in healthy, male Chinese subjects., Methods: Two randomized, single-blind, placebo-controlled, dose-escalation studies were conducted in healthy Chinese men aged 18-45 years. In the single-dose study, subjects received single, oral doses of rivaroxaban 2.5, 5, 10, 20 and 40 mg. In the multiple-dose study, oral rivaroxaban was administered in doses of 5, 10, 20 and 30 mg twice daily for 6 days., Results: Rivaroxaban, in single and multiple doses up to 60 mg, was well tolerated. Rapid absorption was observed in both studies (time to C(max) 1.25-2.5 h). In the multiple-dose study, rivaroxaban exposure increased dose-proportionally after the first dose and at steady state (for the 5-20-mg doses). The half-life of rivaroxaban was up to 7.9 h in the single-dose study. Maximal inhibition of FXa activity was achieved within 1-3 h of dosing in the single-dose study [at 20 mg FXa inhibition as a median percentage change from baseline, 45.92; 95% confidence interval (CI) 44.64, 50.70] and 2-3 h after administration at steady state in the multiple-dose study (at 20 mg median FXa inhibition as a median percentage change from baseline, 60.25; 95% CI 56.16, 63.05), in line with maximum rivaroxaban plasma concentrations., Conclusions: Rivaroxaban demonstrated predictable pharmacokinetics and pharmacodynamics in healthy Chinese subjects, in line with findings observed previously in White subjects. This suggests that fixed doses of rivaroxaban may be administered to all patients, regardless of their ethnic origin.

Rivaroxaban is a novel, oral, direct factor Xa inhibitor for the prevention and treatment of thromboembolic disorders. The objective of this study was to investigate the in vivo metabolism and excretion of rivaroxaban in rats, dogs, and humans. Single doses of [(14)C]rivaroxaban (3 and 1 mg/kg) were administered to rats (orally/intravenously) and dogs (orally), respectively. A single oral dose of [(14)C]rivaroxaban (10 mg) was administered to healthy human males (n = 4). Plasma and excreta were collected and profiled for radioactivity. Recovery of total radioactivity was high and > or = 92% in all species. Unchanged rivaroxaban was the major compound in plasma at all time points investigated, across all species. No major or pharmacologically active circulating metabolites were detected. Rivaroxaban and its metabolites were rapidly excreted; urinary excretion of radioactivity was 25 and 52%, and fecal excretion was 67 and 43% of the dose in rats and dogs, respectively. In humans, 66% of the dose was excreted renally (36% unchanged drug) and 28% in the feces. Radioactivity profiles in excreta were similar across species. Three metabolic pathways were identified: oxidative degradation of the morpholinone moiety (major pathway) and hydrolysis of the central amide bond and of the lactam amide bond in the morpholinone ring (minor pathways). M-1, the main metabolite in excreta of all species, was eliminated via both renal and fecal/biliary routes. In total, 82 to 89% of the dose administered was assigned to unchanged rivaroxaban and its metabolites in the excreta of rats, dogs, and humans.

Objective: 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 (C(max)) 4 h after dosing in all groups. Bioavailability, in terms of the area under the plasma concentration-time curve (AUC) and C(max), 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 inhibition of FXa activity increasing from 68% after rivaroxaban 30 mg to 75% after 40 mg and no further increase with the 50 mg dose. Most adverse events were mild; observed rates were less than placebo for the 30 and 40 mg dose groups, and similar to placebo for 50 mg. No differences were found between male and female subjects. Effects of rivaroxaban doses above 50 mg were not investigated in this study., Conclusions: Each single dose of rivaroxaban was well tolerated, with predictable pharmacokinetics and pharmacodynamics at doses up to 40 mg, and provided effective anticoagulation in healthy elderly subjects. Adverse events were somewhat elevated in the 50 mg group, but given the small sample size, no specific conclusions can be drawn about this dosing level.

Background: Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. Unwanted pro-arrhythmic effects are a common reason for drugs failing to gain regulatory approval; these properties can be detected by assessing the effect of the drug on the QT interval., Objective: This study was performed, in accordance with International Conference on Harmonisation (ICH) E14 guidance, to assess whether rivaroxaban prolongs the QT interval., Study Design: This was a prospective, randomized, double-blind, double-dummy, four-way crossover study., Setting: The study was conducted at a clinical pharmacology research unit., Subjects: Healthy male and female subjects (n = 54) aged > or =50 years were enrolled and remained in the study unit for 3 days for each treatment. Of these, 50 patients were eligible for the QT analysis., Intervention: Subjects received single oral doses of rivaroxaban 45 mg or 15 mg, moxifloxacin 400 mg (positive control), or placebo., Outcome Measures: Multiple ECGs were taken at frequent intervals after drug administration, and the QT interval was measured manually under blinded conditions at a central laboratory. The Fridericia correction formula (QTcF) was used to correct the QT interval for heart rate. The primary outcome was the effect of rivaroxaban or moxifloxacin on the placebo-subtracted QTcF 3 hours after administration. The frequency of outlying QTcF values and the tolerability of the treatments were also assessed., Results: All treatments were well tolerated and had no effect on heart rate. Moxifloxacin established the required assay sensitivity; placebo-subtracted QTcF 3 hours after moxifloxacin administration was prolonged by 9.77 ms (95% CI 7.39, 12.15). Placebo-subtracted QTcF values 3 hours after rivaroxaban administration were -0.91 ms (95% CI -3.33, 1.52) and -1.83 ms (95% CI -4.19, 0.54) with rivaroxaban 45 mg and 15 mg, respectively. QTcF was not prolonged with rivaroxaban at any time, and the frequency of outlying results with rivaroxaban and placebo was similar., Conclusion: This thorough QT study, which was performed in accordance with ICH E14 guidelines, shows that rivaroxaban does not prolong the QTc interval. Therefore, the potential of rivaroxaban for the prevention and treatment of thromboembolic disorders, including chronic cardiovascular disorders, can be investigated in appropriate clinical studies without the need for intensive monitoring of the QTc interval.

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.

Rivaroxaban (Xarelto) is a novel, oral, direct Factor Xa (FXa) inhibitor in late-stage development for the prevention and treatment of thromboembolic disorders. Rivaroxaban inhibits clot-associated and free FXa activity, and prothrombinase activity, and reduces thrombin generation. In animal models, rivaroxaban prevented venous and arterial thrombosis, and was effective at treating venous thrombosis. Rivaroxaban has high oral bioavailability, a rapid onset of action and predictable pharmacokinetics. In phase II studies, rivaroxaban was effective and well tolerated for the prevention of venous thromboembolism (VTE) after major orthopaedic surgery, and for the treatment of deep vein thrombosis. In a phase III study, rivaroxaban demonstrated significantly superior efficacy to enoxaparin for thromboprophylaxis after total knee arthroplasty, with similar low bleeding. Rivaroxaban is also being assessed for the treatment and secondary prevention of VTE, prevention of stroke in patients with atrial fibrillation and secondary prevention in patients with acute coronary syndrome. Rivaroxaban is a promising alternative to current pharmacological agents for thromboembolic disorders.

There are several novel anticoagulants in development that target factor Xa(FXa)-the pivotal point of the coagulation cascade. One promising agent is rivaroxaban (a highly selective, oral, direct FXa inhibitor), which is in advanced clinical development for the prevention and treatment of thromboembolic disorders. Oral rivaroxaban may be given in fixed once-daily doses, with the potential for no coagulation monitoring. These properties, along with results from preclinical and clinical studies, suggest that rivaroxaban may have advantages over current treatments. Studies in arterial and venous animal models demonstrated that rivaroxaban has potent antithrombotic effects, without prolonging bleeding times. In healthy subjects, rivaroxaban was well tolerated, with a predictable pharmacological profile and a low propensity for clinically relevant drug-drug interactions. Phase II studies of rivaroxaban for the prevention of venous thromboembolism (VTE) after major orthopedic surgery support these findings. The results also suggested that a total daily dose range of 5 to 20 mg rivaroxaban had similar efficacy and safety to enoxaparin, and that 10 mg rivaroxaban once daily was the optimal dose. This review assesses the preclinical and clinical characteristics of rivaroxaban, and discusses phase II findings with rivaroxaban for the prevention of VTE after major orthopedic surgery.

Objective: Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa (FXa) inhibitor being developed for the prevention and treatment of thromboembolic disorders. This analysis aimed to define population models for the pharmacokinetics (PK) and pharmacodynamics (PD) ofrivaroxaban in healthy males., Methods: Non-linear, mixed-effect modeling was used to analyze rivaroxaban plasma concentration and PD data (FXa activity and clotting tests) from subjects in a phase I, multiple-ascending-dose study. Subjects received 5 mg rivaroxaban once, twice or three times daily, or 10, 20 or 30 mg rivaroxaban twice daily., Results: The population PK of rivaroxaban were well described by an oral, two-compartment model with first-order absorption and elimination from the central compartment. Population mean estimates for apparent oral clearance and volume of distribution for the central compartment were 9.2 1/h and 55 1, respectively, with moderate inter-individual variability (17.4% and 30.7%, respectively). Total volume of distribution for rivaroxaban at steady state was approximately 70 1. Residual (unexplained) variability was 25%. FXa activity correlated with rivaroxaban plasma concentrations following an inhibitory Emax model; prothrombin time (PT) and rivaroxaban plasma concentrations correlated with a linear model, with a slope of 4.6 s/(100 microg/1). Inter-individual variability was low for the correlation with PT. The models derived were used to define sampling windows for population PK/PD modeling in Phase II studies., Conclusions: This analysis confirms that rivaroxaban has predictable, dose-proportional PK and PD. The linear correlation between rivaroxaban plasma concentrations and PT suggests that this test might be useful to assess rivaroxaban exposure in patients, if required.

Aims: Rivaroxaban (BAY 59-7939) is in advanced clinical development for the prevention and treatment of thromboembolic disorders. Frequent co-medications in the patient populations likely to receive rivaroxaban include NSAIDs. This randomized, two-way crossover study, with a naproxen run-in period, was performed to determine whether naproxen influences the tolerability, pharmacodynamics and pharmacokinetics of rivaroxaban., Methods: Eleven healthy, young males received naproxen 500 mg on two consecutive days, a single dose of rivaroxaban 15 mg, or both., Results: Treatments were well tolerated: adverse events (eight in total), reported by three subjects, were mild and not drug related. Rivaroxaban inhibited Factor Xa activity by 35% and prolonged prothrombin time [by 1.4 times baseline (tb)], activated partial thromboplastin time (1.3 tb) and the HepTest (1.9 tb). Naproxen had no influence on these measures and the combination of rivaroxaban and naproxen did not affect platelet aggregation. Rivaroxaban and naproxen given together significantly increased bleeding time compared with rivaroxaban alone (P = 0.017). However, this difference was small compared with the effect of naproxen given alone, except in one subject. Least squares-means ratios for the AUC and C(max) of rivaroxaban after administration alone and with naproxen were 1.125 [90% confidence interval (CI) 0.995, 1.271] and 1.095 (90% CI 0.905, 1.325), respectively., Conclusions: There appeared to be no clinically relevant interaction between rivaroxaban and naproxen in healthy subjects, although some individuals may be more sensitive to the combination. Large-scale Phase III clinical studies will be required to confirm whether there is an increased risk of bleeding during treatment with rivaroxaban and concomitant NSAIDs.

Anticoagulants are often dose adjusted, or their use restricted, in patients with extremes of body weight. Rivaroxaban (BAY 59-7939) is a novel, oral, direct factor Xa inhibitor in clinical development. This was a randomized, single-blind, placebo-controlled, parallel-group study in healthy male and female subjects to assess the effect of extreme body weight (< or = 50 kg and >120 kg), and gender, on the safety, tolerability, pharmacokinetics, and pharmacodynamics of rivaroxaban 10 mg, compared with subjects of normal weight (70-80 kg). Rivaroxaban was well tolerated. Cmax of rivaroxaban was unaffected in subjects >120 kg but was increased by 24% in subjects weighing < or = 50 kg, resulting in a small (15%) increase in prolongation of prothrombin time, which was not considered clinically relevant. The area under the curve was unaffected by body weight or gender. No other clinically relevant differences were observed, suggesting that rivaroxaban is unlikely to require dose adjustment for body weight or gender.

Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. This was a randomized, 2-way crossover study in healthy male subjects, with an aspirin run-in period, to examine whether aspirin influences the safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban. All treatments were well tolerated; drug-related adverse events were mild and transient. Aspirin did not alter the effects of rivaroxaban on Factor Xa activity or clotting tests. Platelet aggregation and bleeding time were not affected by rivaroxaban, and rivaroxaban did not influence the effects of aspirin on these parameters to a clinically relevant extent. Aspirin did not affect the pharmacokinetics of rivaroxaban, including the fraction unbound. This study suggests that there is no clinically relevant interaction between rivaroxaban and aspirin and that the 2 drugs could be administered concomitantly at the doses used in this study.

To investigate the influence of food and administration of an antacid (aluminum-magnesium hydroxide) or ranitidine on the absorption of BAY 59-7939 (rivaroxaban), 4 randomized studies were performed in healthy male subjects. In 2 food interaction studies, subjects received BAY 59-7939, either as two 5-mg tablets (fasted and fed), four 5-mg tablets (fasted), or one 20-mg tablet (fasted and fed). In 2 drug interaction studies, BAY 59-7939 (six 5-mg tablets) was given alone or with ranitidine (150 mg twice daily, preceded by a 3-day pretreatment phase) or antacid (10 mL). Plasma samples were obtained to assess pharmacokinetic and pharmacodynamic parameters of BAY 59-7939. In the presence of food, time to maximum concentration (t(max)) was delayed by 1.25 hours; maximum concentration (C(max)) and area under the curve (AUC) were increased, with reduced interindividual variability at higher doses of BAY 59-7939. Compared with baseline, BAY 59-7939 resulted in a relative increase in maximum prothrombin time (PT) prolongation of 44% (10 mg) and 53% (20 mg) in the fasted state, compared with 53% and 83% after food. Time to maximum PT prolongation was delayed by 0.5 to 1.5 hours after food, with no relevant influence of food type. No significant difference in C(max) and AUC was observed with coadministration of BAY 59-7939 and ranitidine or antacid.

Objectives: There is a clinical need for safe new oral anticoagulants. The safety, tolerability, pharmacodynamics, and pharmacokinetics of BAY 59-7939--a novel, oral, direct Factor Xa (FXa) inhibitor--were investigated in this single-center, placebo-controlled, single-blind, parallel-group, multiple-dose escalation study., Methods: Healthy male subjects (aged 20-45 years, body mass index 18.6-31.4 kg/m(2)) received oral BAY 59-7939 (n=8 per dose regimen) or placebo (n=4 per dose regimen) on days 0 and 3-7. Dosing regimens were 5 mg once, twice (bid), or three times daily, and 10 mg, 20 mg, or 30 mg bid., Results: There were no clinically relevant changes in bleeding time or other safety variables across all doses and regimens. There was no dose-related increase in the frequency or severity of adverse events with BAY 59-7939. Maximum inhibition of FXa activity occurred after approximately 3 h, and inhibition was maintained for at least 12 h for all doses. Prothrombin time, activated partial thromboplastin time, and HepTest were prolonged to a similar extent to inhibition of FXa activity for all doses. Dose-proportional pharmacokinetics (AUC(tau, norm) and C(max, norm)) were observed at steady state (day 7). Maximum plasma concentrations were achieved after 3-4 h. The terminal half-life of BAY 59-7939 was 5.7-9.2 h at steady state. There was no relevant accumulation at any dose., Conclusions: BAY 59-7939 was safe and well tolerated across the wide dose range studied, with predictable, dose-proportional pharmacokinetics and pharmacodynamics and no relevant accumulation beyond steady state. These results support further investigation of BAY 59-7939 in phase II clinical trials.

Background and Objective: There is a clinical need for new oral anticoagulants to prevent and treat thromboembolic diseases. Given its integral role in the coagulation cascade, factor Xa is a particularly promising target for new anticoagulation therapies. The aim of this study was to investigate the safety, pharmacodynamics, and pharmacokinetics of BAY 59--7939, an oral, direct factor Xa inhibitor., Methods: This single-center, randomized, single-blinded, placebo-controlled, dose-escalation study included 108 healthy white male subjects aged 19 to 45 years. Subjects received single oral doses of either BAY 59--7939 (1.25--80 mg) or placebo; in addition, 1 group received 2 doses of BAY 59--7939 (5--mg tablet and oral solution) or placebo in a crossover design., Results: Oral BAY 59--7939 in single doses up to 80 mg was safe and well tolerated and was not associated with an increased risk of bleeding compared with placebo. Pharmacodynamic effects (inhibition of factor Xa activity, prothrombin time, activated partial thromboplastin time, and Hep Test) and plasma concentration profiles were dose-dependent. Maximum inhibition of factor Xa activity was achieved 1 to 4 hours after administration of BAY 59--7939 and ranged from 20% to 61% for the 5- to 80-mg doses. BAY 59--7939 selectively inhibited factor Xa activity; thrombin (factor IIa) and antithrombin were unaffected. Inhibition of factor Xa activity and prolongation of prothrombin time correlated well with BAY 59--7939 plasma concentrations (r=0.949 and 0.935, respectively)., Conclusions: 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.