title: Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects.
abstract: OBJECTIVE
  Apixaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation and thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and under development for treatment of venous thromboembolism. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple dose apixaban.
  
  
  METHODS
  This double-blind, randomized, placebo-controlled, parallel group, multiple dose escalation study was conducted in six sequential dose panels - apixaban 2.5, 5, 10 and 25 mg twice daily and 10 and 25 mg once daily- with eight healthy subjects per panel. Within each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 days. Subjects underwent safety assessments and were monitored for adverse events (AEs). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT).
  
  
  RESULTS
  Forty-eight subjects were randomized and treated (apixaban, n = 36; placebo, n = 12); one subject receiving 2.5 mg twice daily discontinued due to AEs (headache and nausea). No dose limiting AEs were observed. Apixaban maximum plasma concentration was achieved ~3 h post-dose. Exposure increased approximately in proportion to dose. Apixaban steady-state concentrations were reached by day 3, with an accumulation index of 1.3-1.9. Peak : trough ratios were lower for twice daily vs. once daily regimens. Clotting times showed dose-related increases tracking the plasma concentration-time profile.
  
  
  CONCLUSIONS
  Multiple oral doses of apixaban were safe and well tolerated over a 10-fold dose range, with pharmacokinetics with low variability and concentration-related increases in clotting time measures.
authors: Bristol-Myers Squibb, Princeton, NJ, USA.
authors: Charles
authors: C
authors: Frost
authors: Sunil
authors: S
authors: Nepal
authors: Jessie
authors: J
authors: Wang
authors: Alan
authors: A
authors: Schuster
authors: Wonkyung
authors: W
authors: Byon
authors: Rebecca A
authors: RA
authors: Boyd
authors: Zhigang
authors: Z
authors: Yu
authors: Andrew
authors: A
authors: Shenker
authors: Yu Chen
authors: YC
authors: Barrett
authors: Rogelio
authors: R
authors: Mosqueda-Garcia
authors: Frank
authors: F
authors: Lacreta
mesh_terms: D000284:Administration, Oral; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D011720:Pyrazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D011728:Pyridones / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban
keywords: anticoagulant/thrombolytic drugs; apixaban; cardiovascular pharmacology; coagulation/fibrinolysis; pharmacokinetics