title: Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of apixaban in healthy Japanese male subjects.
abstract: OBJECTIVE
  This was a randomized, placebo-controlled, double-blind, sequential, ascending-dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple oral doses of apixaban in healthy Japanese male subjects.
  
  
  METHODS
  The study was conducted using three sequential dose panels: apixaban 2.5 mg, 5 mg, and 10 mg given twice daily. For each dose panel, subjects were randomly assigned to receive oral apixaban (n = 6) or matching placebo (n = 2) for 7 days. The pharmacokinetics of apixaban and effect on pharmacodynamic variables (clotting assays and anti-Xa activity) were assessed on day 1 and day 7 of treatment. Safety was assessed throughout the study. Only after the preceding dose was confirmed to be safe and well-tolerated subjects were enrolled into the next-higher-dose panel.
  
  
  RESULTS
  Apixaban was safe and well-tolerated in these healthy Japanese male subjects across the doses evaluated. On day 7, peak plasma concentrations were reached ~ 3 hours postdose, and increases in peak plasma concentration (C(max)), trough plasma concentration, and area under the plasma concentration-time curve across one dosing interval (12 hours) were tested dose-proportional across the dose range. A modest degree of accumulation was observed that was similar for all doses (accumulation index of 1.7 to 2.0), and renal clearance was consistent across doses (0.91 L/h - 1.07 L/h). Exposure-dependent prolongation of prothrombin time, activated partial thromboplastin time, modified prothrombin time, and increases in anti-Xa activity were observed after single and multiple doses of apixaban.
  
  
  CONCLUSIONS
  Apixaban was safe and well-tolerated in healthy Japanese subjects. The pharmacokinetic profile of apixaban following multiple twice-daily doses was linear, and exposure parameters such as C(max), observed at ~ 3 hours post-dose, and area under the plasma concentration-time curve increased in a dose-proportional manner. Pharmacodynamic profiles closely followed the apixaban plasma concentration-time profiles.
authors.forename: Naomi
authors.initials: N
authors.lastname: Yamahira
authors.forename: Charles
authors.initials: C
authors.lastname: Frost
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fukase
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Yu
authors.forename: Jessie
authors.initials: J
authors.lastname: Wang
authors.forename: Janice
authors.initials: J
authors.lastname: Pursley
authors.forename: Frank
authors.initials: F
authors.lastname: LaCreta
authors.forename: Masaki
authors.initials: M
authors.lastname: Hiraoka
mesh_terms: D000328:Adult; D004311:Double-Blind Method; D065427:Factor Xa Inhibitors; D006801:Humans; D008297:Male; D011517:Prothrombin Time; D011720:Pyrazoles / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D011728:Pyridones / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban