title: Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects.
abstract: OBJECTIVE
  To evaluate apixaban single dose safety, tolerability, pharmacokinetics and pharmacodynamics and assess the effect of food on apixaban pharmacokinetics.
  
  
  METHODS
  A double-blind, placebo-controlled, single ascending-dose, first-in-human study assessed apixaban safety, pharmacokinetics and pharmacodynamics in healthy subjects randomized to oral apixaban (n = 43; 0.5-2.5 mg as solution or 5-50 mg as tablets) or placebo (n = 14) under fasted conditions. An open label, randomized, two treatment crossover study investigated apixaban pharmacokinetics/pharmacodynamics in healthy subjects (n = 21) administered apixaban 10 mg in fasted and fed states. Both studies measured apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and prothrombin time (PT) or a modified PT (mPT).
  
  
  RESULTS
  In the single ascending-dose study increases in apixaban exposure appeared dose-proportional. Median t(max) occurred 1.5-3.3 h following oral administration. Mean terminal half-life ranged between 3.6 and 6.8 h following administration of solution doses ≤2.5 mg and between 11.1 and 26.8 h for tablet doses ≥5 mg. Concentration-related changes in pharmacodynamic assessments were observed. After a 50 mg dose, peak aPTT, INR and mPT increased by 1.2-, 1.6- and 2.9-fold, respectively, from baseline. In the food effect study: 90% confidence intervals of geometric mean ratios of apixaban C(max) and AUC in a fed vs. fasted state were within the predefined no effect (80-125%) range. Apixaban half-life was approximately 11.5 h. The effect of apixaban on INR, PT and aPTT was comparable following fed and fasted administration.
  
  
  CONCLUSIONS
  Single doses of apixaban were well tolerated with a predictable pharmacokinetic/pharmacodynamic profile and a half-life of approximately 12 h. Apixaban can be administered with or without food.
authors: Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb, Princeton, NJ 08543-4000, USA. charles.frost@bms.com
authors: Charles
authors: C
authors: Frost
authors: Jessie
authors: J
authors: Wang
authors: Sunil
authors: S
authors: Nepal
authors: Alan
authors: A
authors: Schuster
authors: Yu Chen
authors: YC
authors: Barrett
authors: Rogelio
authors: R
authors: Mosqueda-Garcia
authors: Richard A
authors: RA
authors: Reeves
authors: Frank
authors: F
authors: LaCreta
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D004311:Double-Blind Method; D065427:Factor Xa Inhibitors; D005215:Fasting; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D018565:Food-Drug Interactions / Q000502:physiology*; D006207:Half-Life; D006801:Humans; D008297:Male; D011720:Pyrazoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D011728:Pyridones / Q000493:pharmacokinetics* / Q000494:pharmacology; D013997:Time Factors; D055815:Young Adult
chemical_list: D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban