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Introduction This 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 methods Healthy volunteers were randomized to receive once-daily edoxaban 60 mg or 90 mg for 5 days (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 conclusions The 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 60 mg ( P < 0.0001) and 113.0% (107.1–119.2) for edoxaban 90 mg ( 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 5 days. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Edoxaban (the free base of DU-176b) is a new, oral direct Factor Xa inhibitor. This is the first study to compare the hemostatic response to edoxaban, ximelagatran, and dalteparin in healthy, elderly adults. Materials and Methods: In this open-label, active-controlled clinical trial, 40 adults (65-75years), were randomised to: oral edoxaban (60mg, twice-daily, 7 doses), subcutaneous dalteparin (5000IU, once-daily, 4 doses), oral ximelagatran (24mg, twice-daily, 7 doses) or no drug. Blood samples were taken before, and 1.5, 4, 12, 24, 72, 84, 96, 108, 120, and 144 hours after, the first dose. The primary outcomes were changes in thrombin-antithrombin complex, prothrombin fragment 1+2 and D-dimer, and adverse events. Additional biomarkers of coagulation, and endothelial cell and platelet activation were compared (ANOVA). Results: All subjects completed the study. Inhibition of thrombin generation lag time, peak, and constant velocity index were significantly greater, and extended for a longer period of time, following edoxaban administration, compared with dalteparin. We found that the traditional assay for anti-FXa activity was not appropriate for the new anticoagulants. Biomarker changes following edoxaban administration (including prolongation of prothrombin time) reflected inhibition of Factor Xa; there was no effect on platelet, tissue factor or endothelial activation. There were no clinically significant changes in primary outcomes. No serious adverse events were reported. Conclusion: Oral administration of edoxaban resulted in effective Factor Xa and TG inhibition, and was well-tolerated. Studies are needed to confirm edoxaban (60mg daily) use in clinical practice. Sponsorship: Daiichi Sankyo Pharma Development. [ABSTRACT FROM AUTHOR]