Clinical safety, tolerability, pharmacokinetics and pharmacodynamics of the novel factor Xa inhibitor DY-807f in healthy volunteers.

INTRODUCTION: Since Vitamin K antagonists are associated with various limitations such as narrow therapeutic window, slow onset and offset of effect, and numerous interactions with food and drugs, new oral anticoagulants targeted to inhibit thrombin or factor Xa (FXa) have been developed. DY-807f is a highly selective, reversible and orally bioavailable FXa inhibitor. OBJECTIVES: This article describes a first-in-human study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single ascending oral doses of the novel direct FXa inhibitor DY-807f in healthy males. METHODS: a placebo-controlled, single-blinded, randomized, single ascending dose study with 84 subjects (10, 30, 60, 120, 240, and 360 mg). Effects of food and formulation (tablet vs solution) on bioavailability of 60 mg were also assessed as a crossover design. RESULTS: DY-807f doses were safe and well-tolerated with no dose-dependent increase in adverse events up to 360 mg. Pharmacokinetics profiles were consistent across doses with rapid absorption, biphasic elimination, and terminal elimination half-life of 10.5 to 12.4 hours. Coagulation parameters (Activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT)) were linearly correlated with plasma DY-807 (free base of DY-807f) concentrations (correlation coefficient: 0.786 for aPTT, 0.945 for PT). CONCLUSIONS: Single doses of DY-807f are safe and well-tolerated up to 360 mg with predictable pharmacokinetic and pharmacodynamic profiles.

Antithrombin-independent thrombin inhibitors, but not direct factor Xa inhibitors, enhance thrombin generation in plasma through inhibition of thrombin-thrombomodulin-protein C system.

There is increasing concern that some anticoagulants can paradoxically increase thrombogenesis under certain circumstances. Previously, we demonstrated that at certain doses a direct thrombin inhibitor, melagatran, worsens the coagulation status induced by tissue factor (TF) injection in a rat model. We utilised an in vitro thrombin generation (TG) assay to determine if direct thrombin inhibitors could enhance TG in human plasma, and whether inhibition of the negative-feedback system [thrombin-thrombomodulin (TM)-protein C] contributed to the TG enhancement. TG in human plasma was assayed by means of the calibrated automated thrombography. In this assay, direct factor Xa (FXa) inhibitors such as edoxaban and antithrombin (AT)-dependent anticoagulants such as heparin did not increase, but simply suppressed TG. AT-independent thrombin inhibitors (melagatran, lepirudin, and active site blocked thrombin (IIai)) increased peak levels of TG (2.0, 1.6, and 2.2-fold, respectively) in the presence of 12 nM recombinant human soluble TM (rhsTM). Melagatran and lepirudin at higher concentrations began to suppress TG. In the absence of rhsTM, the enhancement of peak TG by melagatran decreased to 1.2-fold. Furthermore, in protein C-deficient plasma, AT-independent thrombin inhibitors failed to enhance TG. In addition, a human protein C neutralising antibody increased the peak height of TG in the presence of rhsTM. These results suggest that AT-independent thrombin inhibitors may activate thrombogenesis by suppression of the thrombin-induced negative-feedback system through inhibition of protein C activation. In contrast, direct FXa inhibitors are more useful than AT-independent thrombin inhibitors in terms of lower possibility of activation of the coagulation pathway.

Different antithrombotic properties of factor Xa inhibitor and thrombin inhibitor in rat thrombosis models.

We compared the antithrombotic properties of a factor Xa inhibitor (DX-9065a) with those of a thrombin inhibitor (melagatran) in a rat disseminated intravascular coagulation model and a rat venous thrombosis model. Rat disseminated intravascular coagulation and venous thrombosis models were produced by injection of tissue factor and platinum wire placement, respectively. DX-9065a exerted antithrombotic effects dose dependently in both models. Melagatran was also effective in the venous thrombosis model, whereas it showed an aggravation in the disseminated intravascular coagulation model at low but not high doses. In the in vitro study, DX-9065a decreased the C(max) of the thrombin generation curve in plasma irrespective of whether protein C was present or not. However, melagatran increased the C(max) at low concentrations when protein C was present. This increase was not detected in protein C-deficient plasma. These results suggest that, unlike DX-9065a, melagatran in low doses aggravates disseminated intravascular coagulation by increasing thrombin generation, which may be partly due to suppression of negative feedback by activated protein C.