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).
Conclusion
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.
Acknowledgments
Study conduct, analysis, and reporting were supported by Dr Maria Velinova and the staff of PRA International, the Netherlands. The authors would like to thank Dr John Alexander for his helpful review of the manuscript. Professional editorial assistance was provided by Andy Shepherd and Dana Fox at Caudex Medical, and funded by Bristol-Myers Squibb Company and Pfizer Inc.
Author contributions
All of the authors (C Frost, Y Song, YC Barrett, J Wang, J Pursley, RA Boyd, and F LaCreta) were: involved in the conception and design (protocol development and/or design advice) and/or acquisition of data (study investigator), or data analysis and interpretation; drafting/revising the publication for content; and approval of the final version to be published.
Disclosure
At the time of research, all authors of this study were employees of Bristol-Myers Squibb Company or Pfizer Inc. This study was sponsored by Bristol-Myers Squibb and Pfizer.