title: First experience with direct factor Xa inhibition in patients with stable coronary disease: a pharmacokinetic and pharmacodynamic evaluation.
abstract: BACKGROUND
  Thrombin generation is critical to the formation of an arterial thrombus after rupture of an atherosclerotic plaque. In patients with stable coronary disease receiving standard medical therapy, we evaluated the pharmacokinetics, pharmacodynamics, and safety profile of DX-9065a, a novel small-molecule anticoagulant that directly, selectively, and reversibly inhibits factor Xa.
  
  
  RESULTS
  In a double-blind trial, 73 patients (median age, 63 years; 29% women) were randomly assigned to receive a fixed-dose intravenous bolus, followed by a 72-hour infusion of placebo or 1 of 4 weight-adjusted regimens of DX-9065a. Plasma samples were collected during infusion and a 24-hour elimination period. Only minor bleeding occurred, predominantly ecchymoses at infusion sites, and its incidence did not differ significantly among the groups, including placebo. Median hemoglobin, platelet count, serum creatinine level, and liver function tests did not change significantly from baseline during infusion or elimination. Significant predictors of pharmacokinetic response included infusion dose and weight. At 60 hours into the DX-9065a infusion, plasma drug levels correlated strongly with anti-factor Xa activity (r=0.97), prothrombin time (r=0.77), and international normalized ratio (r=0.72) but less so with activated partial thromboplastin time (r=0.56; all P<0.001).
  
  
  CONCLUSIONS
  This is the first study of a selective, reversible, and direct small-molecule factor Xa inhibitor in patients with stable coronary disease. These data lay the foundation for further investigation of factor Xa inhibitors in the treatment of patients with coronary atherothrombosis.
authors.affiliation: Duke Clinical Research Institute, Durham, NC 27715, USA.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Dyke
authors.forename: Richard C
authors.initials: RC
authors.lastname: Becker
authors.forename: Neal S
authors.initials: NS
authors.lastname: Kleiman
authors.forename: Judith S
authors.initials: JS
authors.lastname: Hochman
authors.forename: Edwin G
authors.initials: EG
authors.lastname: Bovill
authors.forename: A Michael
authors.initials: AM
authors.lastname: Lincoff
authors.forename: Gary
authors.initials: G
authors.lastname: Gerstenblith
authors.forename: Vladimir
authors.initials: V
authors.lastname: Dzavik
authors.forename: Laura H
authors.initials: LH
authors.lastname: Gardner
authors.forename: Vic
authors.initials: V
authors.lastname: Hasselblad
authors.forename: Linda A
authors.initials: LA
authors.lastname: Zillman
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Shimoto
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Robertson
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kunitada
authors.forename: Paul W
authors.initials: PW
authors.lastname: Armstrong
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harrington
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001241:Aspirin / Q000627:therapeutic use; D015331:Cohort Studies; D003327:Coronary Disease / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015951:Factor Xa / Q000032:analysis; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D007262:Infusions, Intravenous; D019934:International Normalized Ratio; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D010314:Partial Thromboplastin Time; D011422:Propionates / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011517:Prothrombin Time; D013997:Time Factors
chemical_list: C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D000960:Hypolipidemic Agents; D009281:Naphthalenes; D011422:Propionates; D015951:Factor Xa; D001241:Aspirin