A validated LC-MS/MS method for pharmacokinetic study of edoxaban in healthy rabbits
Abstract
A liquid chromatography-tandem mass spectrophotometric (LC–MS/MS) method was developed to quantify Edoxaban in rabbit plasma employing liquid liquid extraction with ethyl acetate. Developed method was validated for specificity, precision, accuracy, recovery, and stability characteristics. Chromatographic separation was achieved on Chromolith C18column (100 mm x 4.6 mm x 5 μm) with 70:30 ratio of methanol and 0.1% formic acid as an isocratic mobile phase with a flow rate of 0.80 mL/min. The developed LC-MS method was applied to assess pharmacokinetics parameters of edoxaban in healthy rabbits. Six Male albino rabbits weighing 2.0-2.5 Kg were randomly selected for the pharmacokinetic study. Blood samples (1-mL) were withdrawn from the marginal ear vein from 0 to 24 hours after administration (1.2 mg/kg). Plasma was separated by centrifugation and the plasma concentrations of edoxaban at various times were determined by LC-MS/MS. Pharmacokinetic parameters was calculated. Edoxaban showed Tmax of 2.0 and mean Cmax, AUC0®t and AUC0®a for Test formulation is 213.83 ± 10.46, 945.13 ± 24.32 and 986.135 ± 19.31, respectively. A highly specific, rugged, and rapid method with sufficiently low LLOQ was developed to analyze routine samples of single dose or multiple-dose pharmacokinetics with any marketing formulation of edoxaban.
Keywords:
Edoxaban, Pharmacokinetics, LC-MS/MS, Rabbit modelDOI
https://doi.org/10.25004/IJPSDR.2022.140112References
Parasrampuria DA, Truitt K.E. (2016) Pharmacokinetics and pharmacodynamics of edoxaban, a non-vitamin K antagonist oral anticoagulant that inhibits clotting factor Xa, Clin. Pharmacokinet; 55:641–655.
SAVAYSA, (2015) (Edoxaban) tablets for oral use, Full Prescribing Information, Daiichi Sankyo Inc., Parsippany, NJ, USA.
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis B.S, Darius H, Diener HC, Joyner CD, Wallentin L. RE-LY Steering Committee and Investigators, (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med; 361: 1139–1151.
Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo A.L, Ezekowitz M.D, Weitz JI, Spinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM, ENGAGE AF-TIMI 48 Investigators (2013), Edoxaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med; 369: 2093–2104.
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al- Khalidi H.R, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton J.D, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser S.H, Horowitz J, Mohan P., Jansky P. ARISTOTLE Committees and Investigators, (2011), Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med; 365: 981–992.
Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H. Segers, (2012) Oral rivaroxaban for the treatment of symptomatic pulmonary embolism, N. Engl. J. Med;366:1287–1297.
Bauersachs R., Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins M.H, Raskob GE, Segers, P. Verhamme A, Wells P, Agnelli G. (2010) Oral rivaroxaban for symptomatic venous thromboembolism. N. Engl. J. Med: 363:2499–2510.
Buller H.R, Decousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong S.M, Schwocho L. (2013) Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N. Engl. J. Med; 369:1406–1415.
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin J.L. ROCKET AF Investigators, (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med: 365;883–891.
Ogata K, Mendell-Harary J, Tachibana M, Masumoto H, Oguma T, Kojima M. (2010) Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol; 50:743-753.
Bathala MS, Masumoto H, Oguma T, He L, Lowrie C, Mendell J. (2012) Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in humans. Drug Metab Dispos; 40:2250-2255.
Gous T, Couchman L, Patel JP, Paradzai C, Arya R, Flanagan RJ. (2014) Measurement of the direct oral anticoagulants apixaban, dabigatran, edoxaban, and rivaroxaban in human plasma using turbulent flow liquid chromatography with high-resolution mass spectrometry. Ther Drug Monit; 36:597-605.
Wan-li Zhang, Dan Lou, Dong-tao Zhang, Yin Zhang, Huan-jie Huang. (2016) Determination of rivaroxaban, apixaban and edoxaban in rat plasma by UPLC–MS/MS method. J Thromb Thrombolysis; 6:1-7
ICH guidelines for the stability of new drug substances and products. Q1A(R2) ICH, Geneva; 2005. p. 1-13.
ICH guidelines for validation of analytical procedures: text and methodology. Q2(R1) ICH, Geneva; 2005. p. 1-14.
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