Plasma Concentrations Of Edoxaban Research Articles

Pharmacokinetics of Edoxaban 15 mg in Very Elderly Patients with Nonvalvular Atrial Fibrillation: A Subanalysis of the ELDERCARE-AF Study.

We evaluated the pharmacokinetics (PK) of low-dose (15 mg) edoxaban in very elderly patients (≥80 years) with nonvalvular atrial fibrillation (NVAF) and high bleeding risk. This subanalysis of the phase 3, randomized, double-blind, placebo-controlled, multicenter ELDERCARE-AF study evaluated edoxaban plasma concentrations and compared them with the Japanese population of the ENGAGE AF-TIMI 48 and Japanese severe renal impairment (SRI) studies. The PK analysis population included 451 patients, 53.8% of whom concomitantly used antiplatelet drugs, 41.0% had SRI, and 38.0% had low body weight. Edoxaban plasma concentrations at trough and 1 to 3 hours post-dose in ELDERCARE-AF were 17.3 ± 13.9 (n = 427) and 93.3 ± 57.8 ng/mL (n = 447), respectively. These values were slightly higher than the 15 mg group in ENGAGE AF-TIMI 48 (n = 79; 12.4 ± 12.1 and n = 115; 78.7 ± 45.0 ng/mL, respectively), lower than the ENGAGE AF-TIMI 48 high-dose reduced to 30 mg group (n = 83; 25.1 ± 36.6 and n = 111; 150 ± 91.6 ng/mL, respectively), but similar to the Japanese SRI study (n = 39; 18.4 ± 11.2 and n = 40; 96.8 ± 48.3 ng/mL, respectively). ELDERCARE-AF patients with SRI and low body weight (≤45 kg) had higher concentrations than those without, and those taking antiplatelet drugs had lower concentrations than those who were not. PK data support edoxaban 15 mg once daily for very elderly NVAF patients with high bleeding risk, with caution for patients with SRI and/or low body weight.

Pharmacokinetics, Pharmacodynamics, and Safety of Edoxaban in Pediatric Subjects: APhase I Single-Dose Study.

This was an open-label, single-dose, phase I study to characterize the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of edoxaban in pediatric subjects from birth to 18 years at risk for venous thromboembolism (VTE). Children requiring anticoagulant therapy were enrolled into 5 age cohorts (0 to < 6 months (N = 12), 0.5 to < 2 years (N = 13), 2 to < 6 years (N = 13), 6 to < 12 years (N = 13), and 12 to < 18 years (N = 15)) receiving tablet or oral suspension of edoxaban at doses expected to be equivalent to 30 or 60 mg once daily (q.d.) in adult subjects with VTE. Sixty-six pediatric subjects were enrolled and completed the study. Edoxaban plasma concentration peaked between 1 and 3 hours and declined rapidly until 4-8 hours. The range of mean total apparent clearance across 5 age cohorts at low and high doses was 0.47 to 1.11 L/h/kg. The ranges of mean volume of central compartment and apparent peripheral volume were 2.31 to 3.59 L/kg and 1.92 to 4.14 L/kg, respectively. Across all age groups, the estimated median exposures were within the 0.5- to 1.5-fold of the median area under the plasma drug concentration-time curve (AUC) in adult subjects receiving corresponding doses (30 mg q.d. for low dose and 60 mg q.d. for high dose). In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time, and anti-Factor Xa activity) showed a linear PK-PD relationship and were in line with previous adult data. The results support further evaluation of the pediatric doses in larger pivotal trials.

PB0492 Review of Edoxaban Plasma Concentrations from King's College Hospital, UK

PB0492 Review of Edoxaban Plasma Concentrations from King's College Hospital, UK

Associations among Plasma Concentrations of Edoxaban and M-4, Prothrombin Time, and the SLCO1B1*15 Haplotype in Patients With Nonvalvular Atrial Fibrillation.

The authors aimed to examine the impact of single nucleotide polymorphisms in P-glycoprotein, the hepatic uptake transporter organic anion transporter protein 1B1, cytochrome P450 ( CYP ) 3A5, and carboxylesterase-1 ( CES1 ) on the steady-state dose-adjusted trough concentrations of edoxaban (C Edo /D) and M-4 (C M-4 /D). They also investigated whether C M-4 and C Edo affect prothrombin time (PT). The analyses included 152 patients with nonvalvular atrial fibrillation (NVAF) undergoing AF catheter ablation. The CYP3A5*3 ; CES1 c.1168-33A>C, c.257+885T>C; SLCO1B1 c.388A>G, c.521T>C; and ABCB1 c.3435C>T, c.2677G>A/T, c.1236C>T genotypes were determined. Stepwise selection multiple linear regression analyses demonstrated that creatinine clearance (Ccr), concomitant use of amiodarone, and SLCO1B1*15 haplotype status were independent factors influencing C M-4 /D (partial R2 = 0.189, 0.098, 0.067, respectively, all P values < 0.005). Ccr and concomitant use of amiodarone were independent factors influencing C Edo /D (partial R2 = 0.260, 0.117, respectively, both P value < 0.001). C Edo and C M-4 showed a weak correlation with PT (ρ = 0.369 and 0.315, both P values < 0.001). Although information concerning Ccr, concomitant use of amiodarone, and SLCO1B1*15 haplotype may be useful in assessing the pharmacokinetics of edoxaban, further studies are needed to clarify the requirement of PT monitoring at the trough level for dose adjustment of edoxaban in patients with NVAF.

Clinical trial assessing the safety of edoxaban with concomitant chemotherapy in patients with gynecological cancer-associated thrombosis (EGCAT study)

BackgroundGynecological cancer is one of the highest risk factors for cancer-associated thrombosis (CAT). Although low-molecular-weight heparin (LMWH) is recommended as an anticoagulant for treating CAT, recent studies have shown that direct oral anticoagulants (DOACs) are an acceptable alternative. Patients with cancer require a series of chemotherapies concomitantly with DOAC administration; however, the extent to which these drugs influence DOAC blood concentrations is unknown. In this study, we measured the plasma concentration of edoxaban during chemotherapy for gynecological cancers to determine its safety.MethodsPatients histologically diagnosed with ovarian or uterine corpus cancer and CAT were recruited after primary surgery and before the initiation of postoperative adjuvant chemotherapy, including paclitaxel. Patients were administered edoxaban (30 or 60 mg) orally for CAT. The plasma concentrations of edoxaban and active factor Xa were determined and their percentage change before and after chemotherapy was calculated. Additionally, blood coagulation tests were analyzed.ResultsSixteen patients with gynecological cancer (12 with ovarian cancer and 4 with uterine corpus cancer) were enrolled. Among these, 15 samples were collected one day after chemotherapy initiation. During chemotherapy, the trough concentration of edoxaban changed from 17.6 ± 10.6 to 20.0 ± 15.6 ng/ml, and the mean percentage change in edoxaban concentration was 14.5%. Therefore, the trough concentrations of edoxaban, which represent excretion capacity, were not significantly increased by chemotherapy with paclitaxel. The area under the plasma edoxaban concentration–time curve and the active factor Xa concentration were also unaffected.ConclusionPatients with CAT and ovarian or uterine corpus cancer administered edoxaban orally showed no significant increase in the trough concentration of edoxaban while undergoing chemotherapy. This suggests the safety of edoxaban use during the treatment of gynecological cancers.Trial registrationEGCAT study; Japan Registry of Clinical Trials, jRCTs051190024.

Feasibility, effectiveness, and safety of edoxaban administration through percutaneous endoscopic gastrostomy: 12-months follow up of the ORIGAMI study.

Edoxaban proved to be safe and effective also in fragile patients, but its administration through percutaneous endoscopic gastrostomy (PEG) has not been previously investigated. The purpose of this study was to evaluate the feasibility and the preliminary safety and efficacy profiles of edoxaban administered via PEG in patients with an indication for long-term oral anticoagulation. ORIGAMI was a prospective, single-arm, observational study (NCT04271293). Patients with PEG and an indication for long-term anticoagulation were prospectively enrolled. Crushed edoxaban at approved doses was administered via PEG. The primary endpoint was the composite of cardio-embolic events consisting of ischemic stroke, systemic embolism, or symptomatic deep venous thrombosis/pulmonary embolism (DVT/PE). Secondary endpoints were the number of bleeding events and edoxaban plasma concentrations at steady state. We here report the 12-month results. A total of 12 patients were enrolled. The main indication for PEG implantation was amyotrophic lateral sclerosis (10/12). The primary endpoint of cardio-embolic events did not occur in any patients at 12 months. All patients were in the therapeutic range of steady-state edoxaban plasma levels. Three minor bleedings were observed, while no major bleedings occurred during the observational period. A total of five patients died. All deaths were from non-cardiovascular causes and were consistent with the natural history of the pre-existing severe disease. Our study suggests that edoxaban administration via PEG is feasible and appears safe and effective in fragile, comorbid patients, resulting in therapeutic plasma concentrations of edoxaban. [ClinicalTrials.gov], identifier [NCT04271293].

How to handle a delayed or missed dose of edoxaban in patients with non-valvular atrial fibrillation? A model-informed remedial strategy.

Edoxaban is a non-vitamin K antagonist oral anticoagulant (NOAC) widely used for the long-term prevention of stroke in patients with non-valvular atrial fibrillation (NVAF). Adherence to NOAC therapy has been unsatisfactory and decreases over time. Remedial strategies are currently used to address the non-adherence events. Current recommendations, however, are generic and not well supported by evidence. The aim of this study was to explore appropriate remedial dosing regimens for non-adherent edoxaban-treated NVAF patients through Monte Carlo simulation. Six regimens were compared with the current recommendations of the European Heart Rhythm Association (EHRA) guide based on total deviation time. Both edoxaban plasma concentration and intrinsic Factor Xa activity were considered. Monte Carlo simulations were performed using RxODE based on a published population pharmacokinetic/pharmacodynamic (PK/PD) model. The proposed remedial strategies were different than the EHRA recommendations and were related to the delay time. However, it was found that the missed dose can be administered immediately if the delay time is within 11 h. When the delay is between 12 and 19 h, a half dose followed by a regular dosing schedule is recommended. When the delay time exceeds 19 h, a full dose followed by a half dose is preferred. PK/PD modelling and simulation are effective in developing and evaluating the remedial strategies of edoxaban, which can help maximise its therapeutic effect.

A Validated LC-MS/MS Method for Pharmacokinetic Study of Edoxaban in Healthy Rabbits

A liquid chromatography-tandem mass spectrophotometric (LC–MS/MS) method was developed to quantify Edoxaban in rabbit plasma employing liquid liquid extraction with ethyl acetate. Developed method was validated for specificity, precision, accuracy, recovery, and stability characteristics. Chromatographic separation was achieved on Chromolith C18column (100 mm x 4.6 mm x 5 µm) with 70:30 ratio of methanol and 0.1% formic acid as an isocratic mobile phase with a flow rate of 0.80 mL/min. The developed LC-MS method was applied to assess pharmacokinetics parameters of edoxaban in healthy rabbits. Six Male albino rabbits weighing 2.0-2.5 Kg were randomly selected for the pharmacokinetic study. Blood samples (1-mL) were withdrawn from the marginal ear vein from 0 to 24 hours after administration (1.2 mg/kg). Plasma was separated by centrifugation and the plasma concentrations of edoxaban at various times were determined by LC-MS/MS. Pharmacokinetic parameters was calculated. Edoxaban showed Tmax of 2.0 and mean Cmax, AUC0®t andAUC0®a for Test formulation is 213.83 ± 10.46, 945.13 ± 24.32 and 986.135 ± 19.31, respectively. A highly specific, rugged, and rapid method with sufficiently low LLOQ was developed to analyze routine samples of single dose or multiple-dose pharmacokinetics with any marketing formulation of edoxaban.

Point-of-care testing for emergency assessment of coagulation in patients treated with direct oral anticoagulants including edoxaban

BackgroundDirect oral anticoagulants (DOAC) including edoxaban are increasingly used for stroke prevention in atrial fibrillation. Despite treatment, annual stroke rate in these patients remains 1–2%. Rapid assessment of coagulation would be useful to guide thrombolysis or reversal therapy in this growing population of DOAC/edoxaban-treated stroke patients. Employing the Hemochron™ Signature Elite point-of-care test system (HC-POCT), clinically relevant plasma concentrations of dabigatran and rivaroxaban can be excluded in a blood sample. However, no data exists on the effect of edoxaban on HC-POCT results.We evaluated whether edoxaban plasma concentrations above the current treatment thresholds for thrombolysis or anticoagulation reversal (i.e., 30 and 50 ng/mL) can be ruled out with the HC-POCT.MethodsWe prospectively studied patients receiving a first dose of edoxaban. Six blood samples were collected from each patient: before, 0.5, 1, 2, 8, and 24 h after drug intake. HC-POCT-based INR (HC-INR), activated clotting time (HC-ACT+ and HC-ACT-LR), activated partial thromboplastin time (HC-aPTT), and mass spectrometry for edoxaban plasma concentrations were performed at each time-point. We calculated correlations, receiver operating characteristics (ROC) and test-specific cut-offs for ruling out edoxaban concentrations > 30 and > 50 ng/mL in a blood sample.ResultsOne hundred twenty blood samples from 20 edoxaban-treated patients were analyzed. Edoxaban plasma concentrations ranged from 0 to 512 ng/mL. HC-INR/HC-ACT+/HC-ACT-LR/HC-aPTT ranged from 0.7–8.3/78–310 s/65–215 s/19–93 s, and Pearson’s correlation coefficients showed moderate to very strong correlations with edoxaban concentrations (r = 0.95/0.79/0.70/0.60). With areas under the ROC curve of 0.997 (95% confidence interval: 0.991–0.971) and 0.989 (0.975–1.000), HC-INR most reliably ruled out edoxaban concentrations > 30 and > 50 ng/mL, respectively, and HC-INR results ≤1.5 and ≤ 2.1 provided specificity/sensitivity of 98.6% (91.2–99.9)/98.0% (88.0–99.9) and 96.8% (88.0–99.4)/96.5% (86.8–99.4).ConclusionsOur study represents the first systematic evaluation of the HC-POCT in edoxaban-treated patients. Applying sufficiently low assay-specific cut-offs, the HC-POCT may not only be used to reliably rule out dabigatran and rivaroxaban, but also very low edoxaban concentrations in a blood sample. Because the assay-specific cut-offs were retrospectively defined, further investigation is warranted.Trial registrationClinicalTrials.gov, registration number: NCT02825394, registered on: 07/07/2016, URL

Changes in plasma concentrations of edoxaban and coagulation biomarkers according to thromboembolic risk and atrial fibrillation type in patients undergoing catheter ablation: Subanalysis of KYU-RABLE.

BackgroundCatheter ablation (CA) for atrial fibrillation (AF) can be associated with a risk of thromboembolism and bleeding. We recently demonstrated that uninterrupted edoxaban with one dose delayed on the CA procedural day is associated with a low risk of periprocedural complications. Previous reports have indicated that some specific subgroups of patients undergoing CA have an increased risk of bleeding and thromboembolic complications. This subanalysis of the KYU‐RABLE study assessed the changes in plasma concentrations of edoxaban and coagulation biomarkers during the periprocedural period of CA in subgroups stratified by the risk of thromboembolism assessed by CHADS2 score (<2 or ≥2) and AF type (paroxysmal AF [PAF] or non‐PAF).MethodsWe evaluated changes in plasma concentrations of edoxaban and coagulation biomarkers (D‐dimer and prothrombin fragment F1+2), by subgroup, during the periprocedural period of CA. Measurements were made prior to CA (procedure day).ResultsThis subanalysis evaluated data from 343 patients with CHADS2 score <2 and 134 patients with CHADS2 score ≥2, and from 280 patients with PAF and 197 patients with non‐PAF. Plasma edoxaban concentration decreased with time on the day of CA, while plasma concentrations of coagulation biomarkers remained unchanged. No significant differences were observed according to CHADS2 score or type of AF.ConclusionsThe changes in plasma concentrations of edoxaban and coagulation biomarkers in each subgroup were similar to those of the whole analysis, regardless of the thromboembolic risk (CHADS2 <2 or ≥2) or AF type (PAF or non‐PAF).

Relationship of Edoxaban Plasma Concentration and Blood Coagulation in Healthy Volunteers Using Standard Laboratory Tests and Viscoelastic Analysis.

The capability of viscoelastic measurement parameters to screen anticoagulation activity of edoxaban in relation to its plasma concentrations was evaluated in 15 healthy male volunteers. Blood samples were drawn before the oral administration of edoxaban 60 mg and 2, 4, 6, 8, and 24 hours after administration. At each time, standard coagulation tests were performed, blood viscoelastic properties were measured with a thromboelastometry device ROTEM delta analyzer (Instrumentation Laboratory, Werfen, Barcelona, Spain), and edoxaban plasma concentrations were measured. Our primary interest was the possible correlation between edoxaban plasma concentrations and values for ROTEM ExTEM, and FibTEM. We also studied the correlation of edoxaban plasma concentrations with the results of standard coagulation tests. We saw the effect of a single dose of edoxaban most clearly in clotting time (CT) of ROTEM ExTEM and FibTEM. Changes in these parameters correlated significantly with edoxaban plasma concentrations up to 6 hours from the ingestion of the drug. Activated partial thromboplastin time, prothrombin time, and anti-factor Xa were also affected. Peak changes were observed 2 and 4 hours after administration of edoxaban. The changes were mostly reversed after 8 hours. In conclusion, ROTEM CT correlates significantly with edoxaban plasma concentrations and can be used to estimate the effect of edoxaban. ROTEM should be considered as part of the assessment of coagulation, with the big advantage of being readily available on site.

Pharmacokinetics of anticoagulant edoxaban in overdose in a Japanese patient transported to hospital

BackgroundThe anticoagulant edoxaban is used clinically at doses of 30–60 mg/day; however, we experienced a patient who had taken an overdose of edoxaban of 750 mg. We investigated the pharmacokinetics of edoxaban in this patient by using liquid chromatography–tandem spectrometry to estimate the follow-up period in emergency clinical practice with this medicine.Case presentationThe patient was a 57-year-old woman (body weight, 69 kg) who had taken a single oral dose of 750 mg of edoxaban in a suicide attempt. She was emergently admitted to Kyoto Medical Center. The patient’s edoxaban plasma concentrations during ambulance transport (8 h after oral administration) were ~ 4900 ng/ml, and the concentration gradually decreased to ~ 10 ng/mL and to detectable but unmeasurable levels of ~ 1.0 ng/mL at 60 h and 100 h, respectively. The linear range of the relationship between the dose and plasma concentration was assumed to have been exceeded during the first 8 h; however, the measured elimination rate of edoxaban was similar to that visualized curves predicted by a simplified physiologically based pharmacokinetic model previously established.ConclusionSimplified physiologically based pharmacokinetic models for creating visualized curves have proven to be useful not only during drug discovery or chemical risk assessment but also in cases of medical poisoning. We used a physiologically based pharmacokinetic model previously established for edoxaban to predict the pharmacokinetics in the current case. It is hoped that the results of this study, which encompass drug monitoring data in the patient and visualized pharmacokinetic prediction, will serve as an index when setting the treatment and follow-up period in cases of drug overdose for medicines such as edoxaban in emergency clinical practice.

Simple LC-MS/MS method using core-shell ODS microparticles for the simultaneous quantitation of edoxaban and its major metabolites in human plasma

Edoxaban is mainly enzymatically converted to a 4-carboxylic acid form (4CA-EDX) and an N-desmethyl form (ND-EDX) in humans. This study aimed to establish a simple liquid chromatography-tandem mass spectrometry method using core-shell octadecyl silica (ODS) microparticles for the simultaneous quantitation of edoxaban and its two major metabolites in human plasma. Analytes extracted from plasma specimens by a one-step deproteinization were separated using a 2.6-µm core-shell ODS microparticulate column and linear acetonitrile-ammonium acetate gradient elution at a flow rate of 0.25 mL/min with a run time of 7 min. The mass spectrometer was operated in the positive ion multiple reaction monitoring mode. Plasma samples collected from 20 patients with atrial fibrillation were analyzed by the present method. The chromatograms of drug-free human plasma had no interfering peaks. The calibration curves of edoxaban, 4CA-EDX, and ND-EDX were linear over the concentration ranges of 1.25–160, 0.47–60, and 0.12–15 ng/mL, respectively. Their pretreatment recoveries and matrix factors were 88.7–109.0% and 87.0–101.6%, respectively. The intra- and inter-day accuracy and imprecision values were 85.9–112.8% and within 13.3%, respectively. The plasma concentrations of edoxaban, 4CA-EDX, and ND-EDX in the patients had ranges of 17.8–102, 1.67–25.7, and 0.685–5.34 ng/mL, respectively. All the analytes were measurable within their calibration curves. In conclusion, this validated method for the simultaneous determination of edoxaban and its major metabolites was successfully applied to plasma specimens obtained from patients with atrial fibrillation.

457Efficacy and safety of uninterrupted periprocedural edoxaban in patients undergoing catheter ablation for atrial fibrillation: Prospective KYU-RABLE study

Abstract Background/Introduction Catheter ablation (CA) has been established as a first-line therapy in the treatment of non-valvular atrial fibrillation (NVAF), and uninterrupted direct oral anticoagulants (DOACs) have become mainstream for the management of periprocedural thromboembolic events. Since 2014, edoxaban has been used for anticoagulation therapy for AF in Japan. However, evidence for uninterrupted use of edoxaban during the periprocedural period of CA in NVAF patients is limited. Purpose KYU-RABLE is a prospective, multicenter, single-arm interventional study, conducted in 23 institutions in Japan to evaluate the efficacy and safety of uninterrupted periprocedural oral edoxaban in patients undergoing CA. The plasma concentration of edoxaban and its relation with plasma coagulative biomarker levels during the periprocedural period were also evaluated. Methods A total of 537 Japanese NVAF patients were enrolled in Japan from December 2017 to September 2018. Edoxaban 60mg (30 mg in patients indicated for dose adjustment) was administered once daily in the morning for at least 4 weeks before CA and continued for at least 4 weeks after CA. On the day of CA, edoxaban was administered immediately after confirmation of hemostat. The primary endpoint was the composite incidence of thromboembolism and major bleeding events during 4 weeks from the procedural day. Plasma concentration of edoxaban and plasma levels of coagulative biomarkers including D-dimer, soluble fibrin monomer complex (SFMC) and prothrombin fragment 1+2 (F1+2) were also measured. Results Among the total 513 patients who underwent CA, 75.2% had radiofrequency CA and 23.0% had cryoballoon CA. The majority of CA patients (65%) received edoxaban 60mg/day, while others (35%) received 30mg/day. As for the primary endpoint, one major bleeding (cardiac tamponade) event was observed and no thromboembolism occurred. Clinically relevant non-major bleeding events occurred in six patients (1.2%), the most were puncture site hemorrhage. The plasma concentration of edoxaban at CA was dependent upon the duration from last administration of edoxaban before CA. However, plasma levels of coagulative biomarkers (D-dimer, SFMC, F1+2) were maintained within appropriate range during the periprocedural period, irrespective of the edoxaban concentration. We also report changes of plasma levels of coagulative biomarkers in sub group analyses by CHADS2 scores and types of AF. Conclusion The KYU-RABLE study demonstrated the first evidence of the efficacy and safety of uninterrupted periprocedural edoxaban administered once daily on the morning for NVAF patients underwent CA. Edoxaban treatment was associated with a low risk of periprocedural bleeding and thromboembolic complications. Furthermore, these low event risks were considered to be associated with the maintained plasma level of coagulative biomarkers, regardless of the change in edoxaban plasma concentration. Acknowledgement/Funding Daiichi Sankyo Co. Ltd.

Linking Endogenous Factor Xa Activity, a Biologically Relevant Pharmacodynamic Marker, to Edoxaban Plasma Concentrations and Clinical Outcomes in the ENGAGE AF-TIMI 48 Trial.

We previously reported exogenous antifactor Xa (FXa) activity as a pharmacokinetic surrogate marker for edoxaban plasma concentrations. Inhibition of endogenous FXa activity is a more biologically relevant pharmacodynamic measure of edoxaban activity. Here we describe the value of endogenous FXa activity as a pharmacodynamic marker linking edoxaban concentrations and clinical outcomes in the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48). In ENGAGE AF-TIMI 48, edoxaban was administered in higher dose (60/30 mg QD) and lower dose (30/15 mg QD) regimens. Both regimens incorporated a 50% dose reduction in patients with characteristics known to increase edoxaban concentration. Pharmacokinetic-pharmacodynamic modeling was performed in a subgroup of 3029 patients who had samples collected for endogenous FXa activity (measured using an assay after endogenous FX was activated with Russell viper venom). Endogenous FXa activity decreased with increasing edoxaban concentrations of ≤440 ng/mL, indicating that inhibition of endogenous FXa activity is saturated above this concentration threshold. Baseline endogenous FXa activity averaged 92.1±20.9% (relative to normal control samples) and was lower with older age, with lower body weight, and in male patients. Model-predicted 24-hour average percentages of inhibition of endogenous FXa activity were 35.8±5.18, 29.1±3.92, 21.9±3.80, and 16.4±2.70 for the higher dose edoxaban regimen 60 mg, dose-reduced higher dose edoxaban regimen 30 mg, lower dose edoxaban regimen 30 mg, and dose-reduced lower dose edoxaban regimen 15 mg groups, respectively. A greater average percentage of inhibition of endogenous FXa activity was associated with a lower incidence of ischemic stroke or systemic embolism and a higher risk of major bleeding ( P<0.001). In a typical subject, the predicted risks for the 10th and 90th percentiles of inhibition of endogenous FXa activity were 1.04% and 0.57% for incidence of ischemic stroke or systemic embolism and 1.35% and 2.33% for major bleeding, respectively. The extent of inhibition of endogenous FXa activity is influenced by edoxaban dosing and clinical characteristics, and it is associated with both antithrombotic benefit and risk of bleeding. This approach of linking endogenous FXa activity to clinical outcomes may be used to guide dose selection in future clinical trials, monitor patients in certain clinical scenarios, or refine the doses of oral FXa inhibitors in patients who require precise anticoagulation therapy. URL: https://www.clinicaltrials.gov . Unique identifier: NCT00781391.

Andexanet alfa effectively reverses edoxaban anticoagulation effects and associated bleeding in a rabbit acute hemorrhage model.

IntroductionIncreasing use of factor Xa (FXa) inhibitors necessitates effective reversal agents to manage bleeding. Andexanet alfa, a novel modified recombinant human FXa, rapidly reverses the anticoagulation effects of direct and indirect FXa inhibitors.ObjectiveTo evaluate the ability of andexanet to reverse anticoagulation in vitro and reduce bleeding in rabbits administered edoxaban.Materials and methodsIn vitro studies characterized the interaction of andexanet with edoxaban and its ability to reverse edoxaban-mediated anti-FXa activity. In a rabbit model of surgically induced, acute hemorrhage, animals received edoxaban vehicle+andexanet vehicle (control), edoxaban (1 mg/kg)+andexanet vehicle, edoxaban+andexanet (75 mg, 5-minute infusion, 20 minutes after edoxaban), or edoxaban vehicle+andexanet prior to injury.ResultsAndexanet bound edoxaban with high affinity similar to FXa. Andexanet rapidly and dose-dependently reversed the effects of edoxaban on FXa activity and coagulation pharmacodynamic parameters in vitro. In edoxaban-anticoagulated rabbits, andexanet reduced anti-FXa activity by 82% (from 548±87 to 100±41 ng/ml; P<0.0001), mean unbound edoxaban plasma concentration by ~80% (from 100±10 to 21±6 ng/ml; P<0.0001), and blood loss by 80% vs. vehicle (adjusted for control, 2.6 vs. 12.9 g; P = 0.003). The reduction in blood loss correlated with the decrease in anti-FXa activity (r = 0.6993, P<0.0001) and unbound edoxaban (r = 0.5951, P = 0.0035).ConclusionThese data demonstrate that andexanet rapidly reversed the anticoagulant effects of edoxaban, suggesting it could be clinically valuable for the management of acute and surgery-related bleeding. Correlation of blood loss with anti-FXa activity supports the use of anti-FXa activity as a biomarker for assessing anticoagulation reversal in clinical trials.

Abstract 98: Point-of-care Testing of Coagulation in Patients Treated With the Non-vitamin K Antagonist Oral Anticoagulant Edoxaban

Introduction: Edoxaban, alongside other non-vitamin K antagonist oral anticoagulants (NOAC), is increasingly used for stroke prevention in patients with atrial fibrillation. Despite treatment, stroke rate in these patients remains one to two percent per year. In this growing population of edoxaban/NOAC-treated stroke patients, rapid assessment of coagulation would be useful to guide the decision for thrombolysis or reversal therapy in case of a neurovascular emergency. However, no data exists on the effect of edoxaban on available point-of-care test (POCT) systems. Hypothesis: Test assays of the commercially available CoaguChek® (CC) and Hemochron® are able to detect clinically relevant concentrations of edoxaban in a blood sample. Methods: We studied patients receiving their first dose of edoxaban. Subjects receiving other anticoagulants were excluded. Six blood samples were collected from each patient: before drug intake, 30 minutes, one, two, and eight hours after intake, as well as before the next dose. Coagulation-POCT and mass spectrometry for gold standard-determination of edoxaban plasma concentration were performed at each time point. Results: 120 blood samples from 20 edoxaban-treated patients were analyzed. Edoxaban concentrations ranged from 0 to 302ng/mL. CC-INR ranged from 0.9 to 2.3. Pearson’s correlation coefficient showed a strong correlation between CC-INR and edoxaban concentrations (r=0.73). Edoxaban concentrations &gt; 30ng/mL (threshold for thrombolysis according to the European Stroke Organisation) were detected by CC-INR ≥ 1.1 with 96% sensitivity and 44% specificity (89% sensitivity and 88% specificity for CC-INR ≥ 1.2; AUC=0.92). Conclusions: Our study represents the first systematic evaluation of coagulation POCT in edoxaban-treated patients. Available coagulation POCT devices may be able to reliably detect clinically relevant edoxaban concentrations in blood samples of stroke patients in the emergency setting. In addition to edoxaban-POCT analyses, we will present further data on NOAC-specific POCT from our SPOCT-NOAC study.

Comparison of three different anti-Xa assays in major orthopedic surgery patients treated with direct oral anticoagulant

BackgroundMeasurement of edoxaban plasma concentration has been gathering attention in major orthopedic surgery patients receiving edoxaban for the prevention of venous thromboembolism (VTE).MethodsThe anti-Xa activity was measured one hour after edoxaban intake using 3 different assays in 200 patients after major orthopedic surgery.ResultsThe anti-Xa activities on Day 8 were significantly higher than those on Day 4 and those on Day 4 were significantly higher than those on Day 1. The anti-Xa activities in two assays closely correlated with each other, but the other anti-Xa assay did not correlated with other two assays. The anti-Xa activities as detected in the three Xa assays were significantly higher in the patients without deep vein thrombosis (DVT) than in those with DVT on Day 4. Additionally, there were no significant differences in the anti-Xa activities of assays A, B and C between patients with and without massive bleeding (MB) on Days 1, 4, 8 and 15.ConclusionThe results of this study suggest that anti-Xa level could be predictive of the risk of VTE, but not of the risk of massive bleeding.

Determination of edoxaban equivalent concentrations in human plasma by an automated anti-factor Xa chromogenic assay

IntroductionThis phase I, open-label, multiple-dose, two-treatment study assessed the relationship between edoxaban equivalent concentration derived from an anti-FXa assay with the summed concentration of edoxaban and its active metabolite, M-4, as assessed by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS). This study also assessed the relationship between edoxaban plasma concentrations assessed by LC/MS/MS in sodium citrate and lithium heparin tubes. Materials and methodsHealthy volunteers were randomized to receive once-daily edoxaban 60mg or 90mg for 5days (15 participants per treatment group). Serial blood samples were collected for analysis by LC/MS/MS and by the anti-FXa assay. Edoxaban equivalent levels were assessed using a commercially available anti-FXa activity assay with an edoxaban-specific setup. Results and conclusionsThe day 5 concentration estimates were significantly correlated between the 2 assays (P<0.0001 for both edoxaban doses). The geometric least squares mean (GLSM) ratio (90% confidence interval) for edoxaban equivalent concentrations vs edoxaban + M-4 concentrations was 114.3% (108.2–120.8) for edoxaban 60mg (P<0.0001) and 113.0% (107.1–119.2) for edoxaban 90mg (P=0.0002). The GLSM ratio for edoxaban concentrations in sodium citrate vs lithium heparin tubes for 60-mg and 90-mg edoxaban doses were 82.8% (78.5–87.3) and 83.9% (79.1–89.0), respectively. In this study, an anti-FXa chromogenic assay with edoxaban-specific calibrators and controls demonstrated good accuracy in estimating edoxaban concentrations across a wide range of concentrations relative to LC/MS/MS at steady state following the administration of once-daily edoxaban for 5days.

A single-dose study investigating the pharmacokinetics and pharmacodynamics of edoxaban at 30–90 mg in healthy Chinese volunteers

1. This study investigated the pharmacokinetics and pharmacodynamics of single-dose edoxaban in healthy Chinese subjects.2. This single-centre, open-label, 3-occasion, cross-over study enrolled six males and six females. Subjects received a single-oral-dose of edoxaban 30–90 mg in each study occasion under fasting condition. Serial blood samples were collected to measure the plasma concentrations of edoxaban and its major active metabolite D21-2393. Meanwhile, PT, INR, aPTT were measured pre- and post-dose. Safety was assessed.3. After administration, edoxaban was rapidly absorbed (median Tmax = 1–2 h). With rapid transformation, peak concentration of D21-2393 was reached within 2-h post-dose. The elimination half-life of edoxaban was 5–20 h. The dose-exposure relationships were slightly lower-than-dose-proportional for both edoxaban and D21-2393. Although women had higher plasma exposure of edoxaban and D21-2393 than men, it was considered clinically insignificant.4. The effects of edoxaban on all pharmacodynamic biomarkers were concentration-dependent and linearly-correlated to plasma level of the compound. Minor bleeding was the most commonly reported adverse events.5. Single oral doses of edoxaban 30–90 mg were safe and well tolerated in healthy Chinese volunteers.6. The pharmacokinetic and pharmacodynamic profiles of edoxaban in Chinese subjects were comparable to those observed in Caucasian and Japanese populations.