title: A randomized direct comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban.
abstract: BACKGROUND
  Currently, there are no direct comparisons of apixaban and rivaroxaban, two new oral direct factor Xa inhibitors approved for management of thromboembolic disorders.
  
  
  OBJECTIVE
  Compare the pharmacokinetics and anti-factor Xa activity (AXA) of apixaban and rivaroxaban.
  
  
  METHODS
  In this randomized, open-label, two-period, two-treatment crossover study, healthy subjects (N=14) received apixaban 2.5 mg twice daily (BID) and rivaroxaban 10 mg once daily (QD) for 4 days with a ≥4.5-day washout. Plasma samples were obtained for pharmacokinetic and AXA assessments; parameters were calculated using noncompartmental methods.
  
  
  RESULTS
  Median time-to-maximum concentration was 2 hours for both compounds, and the mean half-life was 8.7 and 7.9 hours for apixaban and rivaroxaban, respectively. Daily exposure, the area under the curve (AUC(0-24)), appeared similar for rivaroxaban (1,094 ng · h/mL) and apixaban (935 ng · h/mL), whereas mean peak-to-trough plasma concentration ratio was 3.6-fold greater for rivaroxaban (16.9) than apixaban (4.7). Coefficient of variation for exposure parameters (AUC0-24, Cmax, Cmin) was 20%-24% for apixaban versus 29%-46% for rivaroxaban. Peak AXA, AXA AUC(0-24), and AXA fluctuation were ~2.5-, 1.3-, and 3.5-fold higher for rivaroxaban than apixaban, respectively. Trough concentrations and AXA were lower for rivaroxaban (10 ng/mL and 0.17 IU/mL vs 17 ng/mL and 0.24 IU/mL for apixaban, respectively). Rivaroxaban exhibited a steeper concentration-AXA response (slope: 0.0172 IU/ng vs 0.0134 IU/ng for apixaban, P<0.0001).
  
  
  CONCLUSIONS
  Apixaban 2.5 mg BID demonstrated less intersubject variability in exposure, lower AXA AUC, and higher trough and smaller peak-to-trough fluctuations in plasma concentration and AXA, suggesting more constant anticoagulation compared with rivaroxaban 10 mg QD. However, the clinical impact of these differences on the relative efficacy and safety of apixaban and rivaroxaban remains to be determined.
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb Company, Princeton, NJ, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Frost
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb Company, Princeton, NJ, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Song
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb Company, Princeton, NJ, USA.
authors.forename: Yu Chen
authors.initials: YC
authors.lastname: Barrett
authors.affiliation: Exploratory Development Global Biometric Sciences, Bristol-Myers Squibb Company, Princeton, NJ, USA.
authors.forename: Jessie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, Princeton, NJ, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Pursley
authors.affiliation: Global Innovative Pharma Business Clinical Pharmacology, Pfizer Inc., Groton, CT, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Boyd
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb Company, Princeton, NJ, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: LaCreta
keywords: apixaban; pharmacodynamics; pharmacokinetics; rivaroxaban; safety