Characterisation of exposure versus response of edoxaban in patients undergoing total hip replacement surgery

Summary

Edoxaban is an oral direct factor Xa inhibitor approved for the prevention of venous thromboembolism (VTE) in Japan. The objectives of this analysis were to characterise the population pharmacokinetics (PK) of edoxaban and the relationships between edoxaban exposure and clinical outcomes in a phase IIb study of surgical patients following total hip replacement (THR). A total of 1,795 subjects from a phase IIb study, 10 phase I studies, and three phase IIa studies were included in the PK analysis. The exposure-response analysis included data from surgical patients assigned to edoxaban in the phase IIb study. Edoxaban disposition in healthy and post-surgical patients was well-described with a linear, two-compartment model. Creatinine clearance was significantly correlated with edoxaban clearance and the rate of oral absorption was affected by surgery. The probability of a post-operative VTE was significantly correlated with steady-state metrics of edoxaban exposure estimated for each subject by Bayesian post-hoc methods with age and gender being the significant and expected covariates. The incidence of bleeding was low in these studies and hence no exposure-response relationship could be identified. These analyses suggest that edoxaban has a predictable anticoagulant effect in this patient population leading to dose-proportional reduction in incidence of VTE with low incidence of bleeding.

Keywords

Edoxaban - factor Xa inhibitor - population pharmacokinetics - venous thromboembolism

^* Dr. Rohatagi is now with Piramal Life Sciences Ltd, Mumbai, India.

• References

• 1 Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 234S-256S.
• 2 Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet 2009; 48: 1-22.
• 3 Fuji T, Fujita S, Tachibana S. et al. A dose-ranging study evaluating the oral factor Xa inhibitor edoxaban for the prevention of venous thromboembolism in patients undergoing total knee arthroplasty. J Thromb Haemost 2010; 8: 2458-2468.
• 4 Fuji T, Wang CJ, Fujita S. et al. Edoxaban versus enoxaparing for thromboprophylaxis after total knee arthroplasty: The Stars E-3 Trial. Pathophysiol Haemost Thromb 2010; 37: A20 Abstract OC297.
• 5 Ruff CT, Giugliano RP, Antman EM. et al. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: Design and rationale for the effective anticoagulation with factor Xa next generation in atrial fibrillation-thrombolysis in myocardial infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J 2010; 160: 635-641.
• 6 Fuji T, Fujita S, Tachibana S. et al. Efficacy and safety of edoxaban versus enoxaparin for the prevention of venous thromboembolism following total hip arthroplasty: Stars J-V Trial. Blood. 2010 116. Abstract 3320.
• 7 Daiichi sankyo inc.. Comparative investigation of low molecular weight (lmw) heparin/edoxaban tosylate (du176b) versus lmw heparin/warfarin in the treatment of symptomatic deep-vein blood clots and/or lung blood clots.. (The Edoxaban Hokusai-VTE Study). 2012 [cited May 30, 2012]; Available at: http://www.clinicaltrials.gov/ct2/show/NCT00986154?term=edoxaban&rank=1 Accessed May 30, 2012.
• 8 Furugohri T, Isobe K, Honda Y. et al. DU-176b, a potent and orally active factor Xa inhibitor: In vitro and in vivo pharmacological profiles. J Thromb Haemost 2008; 6: 1542-1549.
• 9 Ogata K, Mendell-Harary J, Tachibana M. et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol 2010; 50: 743-753.
• 10 Matsushima N, Lee F, Sato T. et al. Absolute bioavailability of edoxaban in healthy subjects. AAPS J 2011; 13 (Suppl. 02) T2362.
• 11 Mendell J, Basavapathruni R, Swearingen D. et al. A thorough electrocardiogram study of edoxaban, a novel factor Xa inhibitor. J Clin Pharmacol 2011; 51: 1241-1246.
• 12 Mendell J, Noveck RJ, Shi M. Pharmacokinetics of the direct factor Xa inhibitor edoxaban and digoxin administered alone and in combination. J Cardiovasc Pharmacol. 2012 epub ahead of print.
• 13 Matsushima N, Mendell J, Zahir H. et al. Effects of quindine on pharmacokinetics (PK) of oral (po) and intravenously (iv) administered edoxaban. Clin Pharmacol Ther 2011; 91: S34 Abstract P-72.
• 14 Mendell J, Noveck RJ, Shi M. A randomized trial of the safety, pharmacokinetics, and pharmacodynamics of edoxaban, an oral factor Xa inhibitor, following a switch from warfarin. Br J Clin Pharmacol 2012; Epub ahead of print
• 15 Zahir H, Matsushima N, Halim AB. et al. Edoxaban administration following enoxaparin: A pharmacodynamic, pharmacokinetic, and tolerability assessment in human subjects. Thromb Haemost 2012; 108: 166-175.
• 16 Raskob G, Cohen AT, Eriksson BI. et al. Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement. A randomised double-blind dose-response study. Thromb Haemost 2010; 104: 642-649.
• 17 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31-41.
• 18 Tunblad K, Lindbom L, McFadyen L. et al. The use of clinical irrelevance criteria in covariate model building with application to dofetilide pharmacokinetic data. J Pharmacokinet Pharmacodyn 2008; 35: 503-526.
• 19 Lindbom L, Pihlgren P, Jonsson EN. PsN-Toolkit--a collection of computer intensive statistical methods for non-linear mixed effect modeling using nonmem. Comput Methods Programs Biomed 2005; 79: 241-257.
• 20 Kennedy JM, Riji AM. Effects of surgery on the pharmacokinetic parameters of drugs. Clin Pharmacokinet 1998; 35: 293-312.
• 21 Eriksson BI, Borris LC, Dahl OE. et al. A once-daily, oral, direct factor Xa inhibitor, rivaroxaban (BAY 59–7939), for thromboprophylaxis after total hip replacement. Circulation 2006; 114: 2374-2381.
• 22 Eriksson BI, Dahl OE, Buller HR. et al. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 2005; 3: 103-111.
• 23 Lassen MR, Davidson BL, Gallus A. et al. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost 2007; 5: 2368-2375.
• 24 Salazar DE, Mendell J, Kastrissios H. et al. Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation. Thromb Haemost 2012; 107: 925-934.
• 25 Sankyo Daiichi. launches Lixiana^® (edoxaban), a direct oral factor Xa inhibitor, in japan for the prevention of venous thromboembolism after major orthopedic surgery. Available at: Http://dsi.Com/c/document_library/get_file?Uuid=c2711027–5c50–4af7–95d4-de3e0354b23f&groupid=12065&wt.Z_oss_s=1 2011 Accessed July 26, 2012.
• 26 Leil TA, Feng Y, Zhang L. et al. Quantification of apixaban's therapeutic utility in prevention of venous thromboembolism: Selection of phase III trial dose. Clin Pharmacol Ther 2010; 88: 375-382.
• 27 Lassen MR, Raskob GE, Gallus A. et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009; 361: 594-604.
• 28 Lassen MR, Raskob GE, Gallus A. et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): A randomised double-blind trial. Lancet 2010; 375: 807-815.
• 29 Eriksson BI, Borris L, Dahl OE. et al. Oral, direct factor Xa inhibition with BAY 59–7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006; 4: 121-128.
• 30 Mueck W, Borris LC, Dahl OE. et al. Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost 2008; 100: 453-461.
• 31 Xarelto^® (rivaroxaban) tablets. Full prescribing information. Janssen Pharmaceutical, Inc., Titusville, New Jersey; 2011
• 32 Xarelto^® (rivaroxaban) tablets. Full prescribing information. Bayer Pharmer AG, Berlin, Germany; 2009
• 33 Koretsune Y, Inoue H, Kawai Y. et al. The oral factor Xa inhibitor DU-176b in Japanese warfarin-naive patients with atrial fibrillation: Results of two phase II open-label, dose-escalation studies. J Am Coll Cardiol. 2009 53. Abstract 430.
• 34 Mendell J, Shi M. Safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of edoxaban in healthy post-menopausal or surgically sterile females, and healthy elderly males. Eur Heart J 2011; 32: 461.
• 35 Wolzt M, Samama MM, Kapiotis S. et al. Effect of edoxaban on markers of coagulation in venous and shed blood compared with fondaparinux. Thromb Haemost 2011; 105: 1080-1090.
• 36 Mendell J, Tachibana M, Shi M. et al. Effects of food on the pharmacokinetics of edoxaban, an oral direct factor Xa inhibitor, in healthy volunteers. J Clin Pharmacol 2011; 51: 687-694.
• 37 Samama MM, Kunitada S, Oursin A. et al. Comparison of a direct factor Xa inhibitor, edoxaban, with dalteparin and ximelagatran: A randomised controlled trial in healthy elderly adults. Thromb Res 2010; 126: e286-e293.
• 38 Mendell J, Lasseter K, Shi M. Effect of esomeprazole on edoxaban pharmacokinetics and pharmacodynamics when administered orally as tablet and as solution. Europace. 2011 13. Abstract P1052.
• 39 Mendell J, Lee F, Chen S. et al. Effect of low-dose and high-dose aspirin on the pharmacokinetics and pharmacodynamics of edoxaban. Basic Clin Pharmacol Toxicol 2010; 107: 162-962. Abstract 2846.