Rivaroxaban In Healthy Subjects Research Articles

Bioequivalence study of two formulations of rivaroxaban in healthy adult subjects under fasting conditions

Objectives: Oral anticoagulants exert their antithrombotic effect by disrupting the coagulation cascade. Rivaroxaban is the first oral agent to be developed that inhibits the coagulation process by binding directly to Factor Xa in a competitive manner. The aim of this study was to demonstrate the bioequivalence (BE) and safety of a generic formulation of rivaroxaban by comparing their pharmacokinetic (PK) parameters through statistical data and criteria of validation. Oral tablet formulations of 20 mg of a commercial product rivaroxaban reference (R) were tested against a generic product test (T) in 24 healthy adults under fasting condition. Materials and Methods: The study was an open label, balanced, randomized, two-treatment, two-period, two-sequence, single oral dose, and crossover study. Blood samples were collected pre-dose and at specified intervals up to 48-h post-dose to evaluate PK parameters by quantifying the concentration of rivaroxaban in plasma using a validated Liquid chromatography-mass spectrometry (LC-MS/MS) method of analysis. Statistics and confidence intervals (CIs) were calculated for BE purposes. Results: The geometric means of the T/R ratios and 90% confidence intervals (CIs) were: Cmax 87.80% (82.74 –93.12%), AUC0-t 85.96% (81.88–90.24%), and AUC0-∞ 86.13% (82.2–90.35%). All PK parameters are within BE acceptance range of 80–125% for demonstration of average bioequivalence. Conclusions: The study demonstrates the BE and well tolerance of both formulations of rivaroxaban in healthy subjects under fasting conditions.

Single and Repeated Doses of EGb 761® do not Affect Pharmacokinetics or Pharmacodynamics of Rivaroxaban in Healthy Subjects

The present drug-drug interaction study investigates whether single or repeated doses of 240 mg Ginkgo biloba extract EGb 761® alter the pharmacokinetics or pharmacodynamics of rivaroxaban in healthy subjects. This was a single-centre, two-period, fixed-sequence trial. In Period 1, rivaroxaban was taken alone. In Period 2, rivaroxaban was given on the first and last of 8 days of EGb 761® treatment. Plasma concentrations of rivaroxaban and anti-Factor Xa activity were determined until 48 h after each rivaroxaban intake. The data of forty-one healthy subjects (25 males, 16 females) aged 21–70 years were evaluable. Geometric mean ratios (90% confidence intervals) for rivaroxaban administered concomitantly with a single or multiple doses of EGb 761® vs. rivaroxaban administered alone were 97.97 (91.78, 104.58) and 96.78 (90.67, 103.31) for maximum concentration (Cmax), 98.55 (94.43, 102.84) and 97.82 (93.73, 102.08) for area under the concentration-time curve (AUC0-∞) of rivaroxaban in plasma (primary endpoints), 98.19 (92.00, 104.80) and 99.78 (93.43, 106.55) for maximum effect (Emax), 99.46 (93.63, 105.66) and 99.12 (93.25, 105.35) for area under the effect curve (AUEC0-48). All 90% confidence intervals were within the prespecified range of 80%–125%. Neither adverse events related to haemorrhages nor clinically significant findings in haematology or coagulation parameters were observed. The treatments were safe and well-tolerated. Single and repeated doses of EGb 761® neither affect plasma concentrations of rivaroxaban nor anti-Factor Xa activity in healthy subjects.

10 Efficacy and Safety of Ciraparantag in Reversing Apixaban and Rivaroxaban as Measured by Whole Blood Clotting Time in Healthy Adults

There is an unmet need for agents that can rapidly reverse the effects of the direct oral anticoagulants (DOACs) in emergency settings. Ciraparantag, an anticoagulant reversal agent with broad activity, binds directly to anticoagulant molecules including DOACs, enoxaparin and unfractionated heparin, without binding to endogenous coagulation factors or other plasma proteins. Ciraparantag has been shown to reverse anticoagulation in healthy volunteers treated with edoxaban and enoxaparin, as measured by whole blood clotting time (WBCT). Two Phase 2 studies evaluated the efficacy (measured by WBCT) and safety of ciraparantag for reversal of anticoagulation induced by apixaban or rivaroxaban in healthy adults. Two randomized, placebo-controlled, dose-ranging studies were conducted in healthy subjects 50-75 years of age. In each study, subjects received anticoagulant (apixaban or rivaroxaban) until steady state. Study 1 subjects received apixaban 10 mg orally twice daily for 3.5 days. Study 2 subjects received rivaroxaban 20 mg orally once daily for 3 days. In both studies, subjects at steady-state anticoagulation were randomized 3:1 to a single IV dose of ciraparantag (Study 1: 30, 60, or 120 mg; Study 2: 30, 60, 120 or 180 mg) or placebo. Efficacy was based on manual WBCT at multiple timepoints over 24 hours. Subjects and technicians performing the WBCT testing were blinded to treatment. In Study 1, 49 subjects were randomized to receive study drug (36 ciraparantag, 13 placebo) and completed the study as planned. In Study 2, 64 subjects were randomized to receive study drug (48 ciraparantag, 16 placebo) and all but one subject (who had an unrelated adverse event) completed the study as planned. In both studies, ciraparantag demonstrated a rapid (within 15 minutes after infusion) and dose-dependent reversal of anticoagulation compared with placebo. In both studies, analysis of least squares mean WBCT values showed statistically significant differences between each ciraparantag group and placebo. Among subjects who were anticoagulated, reversal of WBCT to ≤10% of baseline within 1 hour post-dose and sustained through at least 5 hours was observed in 67%, 100%, 100% with escalating doses of apixaban, and 17% of placebo subjects; and in 58%, 75%, 67% and 100% with escalating dose of rivaroxaban and 13% of placebo subjects. Ciraparantag was well tolerated; the most common adverse events were mild, transient sensations of warmth (typically reported as hot flashes or flushing), which were dose related. Ciraparantag, after a single IV dose, resulted in a dose-dependent reversal of the anticoagulant effect induced by steady-state dosing of apixaban or rivaroxaban in healthy subjects, as determined by manual WBCT testing. The effect was sustained through at least 5 hours after dosing, and ciraparantag was well tolerated.

IN VIVO REVERSAL OF THE ANTICOAGULANT EFFECT OF RIVAROXABAN WITH 4-FACTOR PROTHROMBIN COMPLEX CONCENTRATE

Rivaroxaban lacks a specific reversal agent. Fifty units/kg of 4-factor prothrombin complex concentrate (PCC, Cofact®) completely reversed the anticoagulant effect of rivaroxaban in healthy subjects (Eerenberg, Circulation 2011;124:1573). We hypothesized that infusion with doses of 37.5 or 25 units

The Influence of Age and Gender on the Pharmacokinetics and Pharmacodynamics of Rivaroxaban—An Oral, Direct Factor Xa Inhibitor

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.

Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate

Background— Rivaroxaban and dabigatran are new oral anticoagulants that specifically inhibit factor Xa and thrombin, respectively. Clinical studies on the prevention and treatment of venous and arterial thromboembolism show promising results. A major disadvantage of these anticoagulants is the absence of an antidote in case of serious bleeding or when an emergency intervention needs immediate correction of coagulation. This study evaluated the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of these drugs. Methods and Results— In a randomized, double-blind, placebo-controlled study, 12 healthy male volunteers received rivaroxaban 20 mg twice daily (n=6) or dabigatran 150 mg twice daily (n=6) for 2½ days, followed by either a single bolus of 50 IU/kg PCC (Cofact) or a similar volume of saline. After a washout period, this procedure was repeated with the other anticoagulant treatment. Rivaroxaban induced a significant prolongation of the prothrombin time (15.8±1.3 versus 12.3±0.7 seconds at baseline; P <0.001) that was immediately and completely reversed by PCC (12.8±1.0; P <0.001). The endogenous thrombin potential was inhibited by rivaroxaban (51±22%; baseline, 92±22%; P =0.002) and normalized with PCC (114±26%; P <0.001), whereas saline had no effect. Dabigatran increased the activated partial thromboplastin time, ecarin clotting time (ECT), and thrombin time. Administration of PCC did not restore these coagulation tests. Conclusion— Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study. Clinical Trial Registration— URL: http://www.trialregister.nl . Unique identifier: NTR2272.

The Effect of Extreme Age, and Gender, on the Pharmacology and Tolerability of Rivaroxaban - An Oral, Direct Factor Xa Inhibitor.

Anticoagulants, such as warfarin, are indicated for a variety of medical conditions, some of which are strongly age dependent. In younger people, the prevalence of many cardiovascular diseases is typically higher in males; however, with increasing age, this difference often resolves. Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa (FXa) inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. This randomized, single-blind study was performed to investigate the influences of age and gender on the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of rivaroxaban in healthy subjects. Four subject groups (young males or females, aged 18–45 years, and elderly males or females, aged >75 years) received a single dose of rivaroxaban 10 mg or placebo (N=34). Gender had no effect on the area under the plasma concentration-time curve (AUC), or maximum plasma concentration (Cmax) of rivaroxaban (Table); however, elderly subjects had higher AUC values than young subjects (least-squares mean ratio [LS-mean] 1.41, 90% confidence interval [CI] 1.20–1.66). The Cmax of rivaroxaban was unaffected by age (LS-mean 1.08, 90% CI 0.96–1.25). Total and renal clearance of rivaroxaban correlated positively with creatinine clearance (CrCL), and inversely with age. The patterns of inhibition of FXa activity by rivaroxaban for all groups were mirrored by those of prolongation of prothrombin time (PT); the maximum effect (Emax) of both consistently occurred 2–4 hours after administration and was unaffected by age or gender. In parallel with the PK results, the AUC of the PD effect, from administration of rivaroxaban to the final time point (AUC0-tn), was increased in elderly subjects (inhibition of FXa activity, LS-mean 1.58, 90% Cl 1.32–1.89; prolongation of PT, LS-mean 1.46, 90% Cl 1.29–1.66); however, all values returned to within 10% of baseline 24 hours after administration of rivaroxaban. The AUC0-tn values correlated inversely with CrCL. Rivaroxaban was well tolerated by all groups; the incidence and intensity of adverse events was similar to placebo. In conclusion, these results demonstrate that the observed effect of age on the PK and PD of this rivaroxaban dose - increased AUC in elderly subjects - was largely due to reduced renal function. Gender had virtually no effect on the PK and PD of rivaroxaban, and neither age nor gender affected tolerability. These findings suggest that rivaroxaban, at similar doses, may not require dose adjustment in elderly patients, or for gender. Phase II studies of rivaroxaban for the prevention of venous thromboembolism also suggested that dose adjustment may not be required for age or gender in this indication. However, this will require confirmation in large-scale phase III studies.PK and PD parameters in subjects receiving rivaroxaban 10 mg (n=6 in each group)Young malesYoung femalesElderly malesElderly femalesAUC (μg·h/L)1477/29.971210/12.691839/28.241941/16.15Cmax (μg/L)227.57/18.25209.73/23.95228.80/23.79245.01/18.23Inhibition of FXaEmax (%)50.86/16.8453.99/12.4456.30/6.3960.16/9.01AUC0-tn (%/h)432.76/38.75343.14/24.61613.94/11.09596.48/23.20Prolongation of PTEmax (x-fold)1.62/9.061.69/8.491.66/5.671.75/4.63AUC0-tn (x-fold/h)22.69/28.0915.98/10.4129.77/3.1526.06/17.52Values are geometric means/geometric coefficients of variation (%)