• 1. Liu SK. Pathology of feline heart disease. Vet Clin North Am 1977; 7: 323339.

  • 2. Tilley LP, Liu SK, Gilbertson SR, et al. Primary myocardial disease in the cat: a model for human cardiomyopathy. Am J Pathol 1977; 86: 493522.

    • Search Google Scholar
    • Export Citation
  • 3. Laste NJ, Harpster NK. A retrospective study of 100 cases of feline distal aortic thromboembolism: 1977–1993. J Am Anim Hosp Assoc 1995; 31: 492500.

    • Search Google Scholar
    • Export Citation
  • 4. Pion PD, Kittleson MD. Therapy for feline aortic thromboembolism. In: Kirk RW, ed. Kirk's current veterinary therapy X: small animal practice. Philadelphia: WB Saunders Co, 1989; 295302.

    • Search Google Scholar
    • Export Citation
  • 5. Harpster NK, Baty CS. Warfarin therapy of the cat at risk of thromboembolism. In: Bonagura JD, ed. Kirk's current veterinary therapy XII: small animal practice. Philadelphia: WB Saunders Co, 1995; 868873.

    • Search Google Scholar
    • Export Citation
  • 6. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981992.

    • Search Google Scholar
    • Export Citation
  • 7. Frost C, Wang J, Nepal S, et al. Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Br J Clin Pharmacol 2013; 75: 476487.

    • Search Google Scholar
    • Export Citation
  • 8. Menke J, Luthie L, Kastrup A, et al. Thromboembolism in atrial fibrillation. Am J Cardiol 2010; 105: 502510.

  • 9. Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrillation: Virchow's triad revisited. Lancet 2009; 373: 155166.

    • Search Google Scholar
    • Export Citation
  • 10. Hart RG, Benavente O, McBride R, et al. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation. Ann Intern Med 1999; 131: 492501.

    • Search Google Scholar
    • Export Citation
  • 11. Büller HR, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thrombotic disease. Chest 2004; 126: 401S428S.

  • 12. Sabir IN. Antithrombotic therapy in atrial fibrillation: aspirin is rarely the right choice. Postgrad Med J 2013; 89: 346351.

  • 13. Lassen MR, Gallus A, Raskob GE, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010; 363: 24872498.

    • Search Google Scholar
    • Export Citation
  • 14. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368: 699708.

  • 15. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: 806817.

  • 16. He K, Luetgen JM, Zhang D, et al. Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor. Eur J Drug Metab Pharmacokinet 2011; 36: 129139.

    • Search Google Scholar
    • Export Citation
  • 17. Zhang D, He K, Raghavan N, et al. Comparative metabolism of 14C-labeled apixaban in mice, rats, rabbits, dogs and humans. Drug Metab Dispos 2009; 37: 17381748.

    • Search Google Scholar
    • Export Citation
  • 18. Zhang D, He K, Raghavan N, et al. Metabolism, pharmacokinetics and pharmacodynamics of the factor Xa inhibitor apixaban in rabbits. J Thromb Thrombolysis 2010; 29: 7080.

    • Search Google Scholar
    • Export Citation
  • 19. Raghavan N, Frost CE, Yu Z, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 2009; 37: 7481.

    • Search Google Scholar
    • Export Citation
  • 20. Delavenne X, Mismetti P, Basset T. Rapid determination of apixaban concentration in human plasma by liquid chromatography/tandem mass spectrometry: application to pharmacokinetic study. J Pharm Biomed Anal 2013; 78–79:150153.

    • Search Google Scholar
    • Export Citation
  • 21. Moll S, Ortel TL. Monitoring warfarin therapy in patients with lupus anticoagulants. Ann Intern Med 1997; 127: 177185.

Advertisement

Pharmacokinetics and pharmacodynamics of the factor Xa inhibitor apixaban after oral and intravenous administration to cats

View More View Less
  • 1 Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523.
  • | 2 Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523.
  • | 3 Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523.
  • | 4 Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523.
  • | 5 Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523.

Abstract

OBJECTIVE To determine pharmacokinetic and pharmacodynamic properties of the novel factor Xa inhibitor apixaban in clinically normal cats.

ANIMALS 5 purpose-bred domestic shorthair cats.

PROCEDURES A single dose of apixaban (0.2 mg/kg, PO) was administered to each cat (time 0), and blood samples were obtained at 0, 15, 30, 45, 60, 120, 240, 360, 480, and 1,440 minutes. After a 1-week washout period, another dose of apixaban (0.2 mg/kg, IV) was administered to each cat, and blood samples were obtained at 0, 5, 10, 15, 30, 45, 60, 120, 240, 360, 480, and 1,440 minutes. Apixaban concentrations in plasma were measured via liquid chromatography–tandem mass spectrometry. Pharmacodynamic effects of apixaban were determined with a commercial assay for factor × activity, which measures endogenous factor Xa activity chromogenically.

RESULTS Factor Xa was inhibited as a function of time after a single dose of apixaban administered orally or IV, and a direct inverse correlation with the plasma apixaban concentration was detected. Pharmacokinetic analysis revealed moderate clearance, short half-life, and high bioavailability for apixaban. A 2-compartment model was fit to the IV pharmacokinetic data; compartmental modeling could not be used to adequately describe the oral data because of substantial interindividual variability.

CONCLUSIONS AND CLINICAL RELEVANCE Results inticated that apixaban was an effective inhibitor of factor Xa in cats. Further studies will be needed to determine pharmacokinetics and pharmacodynamics after multidose administration, effects of cardiac disease on pharmacokinetics and pharmacodynamics, dosing recommendations, and efficacy of apixaban for use in the treatment and prevention of thromboembolic disease in cats.

Contributor Notes

Dr. Myers’ present address is Triangle Veterinary Referral Hospital, 608 Morreene Rd, Durham, NC 27705.

Address correspondence to Dr. Bright (jmbright@colostate.edu).