title: Impact of nonsynonymous mutations of factor X on the functions of factor X and anticoagulant activity of edoxaban.
abstract: Edoxaban is an oral direct factor Xa (FXa) inhibitor and its efficacy as an oral anticoagulant is less subject to drug-food and drug-drug interaction than existing vitamin K antagonists. Although this profile of edoxaban suggests it is well suited for clinical use, it is not clear whether genetic variations of factor X influence the activity of edoxaban. Our aim was to investigate a possible impact of single-nucleotide polymorphisms (SNPs) in the factor X gene on the functions of factor X and the activity of edoxaban. Two nonsynonymous SNPs within mature factor X, Ala152Thr and Gly192Arg, were selected as possible candidates that might affect the functions of FXa and the activity of edoxaban. We measured catalytic activities of wild type and mutant FXas in a chromogenic assay using S-2222 and coagulation times including prothrombin time (PT) and activated partial thrombin time (aPTT) of plasma-containing recombinant FXs in the presence and absence of edoxaban. Michaelis-Menten kinetic parameters of FXas, Km and Vmax values, PT and aPTT were not influenced by either mutation indicating these mutations do not affect the FXa catalytic and coagulation activities. The Ki values of edoxaban for the FXas and the concentrations of edoxaban required to double PT and aPTT were not different between wild type and mutated FXas indicating that both mutations have little impact on the activity of edoxaban. In conclusion, these data suggest that edoxaban has little interpatient variability stemming from SNPs in the factor X gene.
authors.affiliation: aThe Keio-Daiichi Project on Genetics of Thrombosis, Keio University bBiological Research Laboratories cNew Drug Regulatory Affairs Department dResearch Oversight Function, R&D Division, Daiichi Sankyo Co., Ltd eLaboratory Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Noguchi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Morishima
authors.forename: Shinichi
authors.initials: S
authors.lastname: Takahashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ishihara
authors.forename: Toshiro
authors.initials: T
authors.lastname: Shibano
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Murata
mesh_terms: D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects* / Q000235:genetics*; D001780:Blood Coagulation Tests; D005170:Factor X / Q000235:genetics* / Q000378:metabolism; D065427:Factor Xa Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D011725:Pyridines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; D005170:Factor X; C552171:edoxaban