Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation

Summary

Edoxaban is a novel, orally available, highly specific direct inhibitor of factor Xa and is currently being developed for the treatment and prevention of venous thromboembolism and prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). The objectives of the present analyses were to characterise edoxaban population pharmacokinetics (PPK) and identify potential intrinsic and extrinsic factors affecting variability in edoxaban exposure, determine if there are relationships between edoxaban pharmacokinetics or biomarkers and the risk of bleeding in patients with NVAF using an exposure-response model, and to use the PPK and exposure-response model to support dose selection for a phase III trial of edoxaban in patients with NVAF. PPK analysis of data from 1,281 edoxaban-dosed subjects with intrinsic factors such as renal impairment or NVAF and extrinsic factors such as concomitant medications revealed significant effects of renal impairment and concomitant strong P-glycoprotein (P-gp) inhibitors on the pharmacokinetics of edoxaban. Exposure-response analysis found that in patients with NVAF, the incidence of bleeding events increased significantly with increasing edoxaban exposure, with steady-state minimum concentration (C_min,ss) showing the strongest association. Clinical trial simulations of bleeding incidence were used to select 30 mg and 60 mg once-daily edoxaban with 50% dose reductions for patients with moderate renal impairment or receiving concomitant strong P-gp inhibitors as the treatment regimens in the ENGAGE AF-TIMI 48 (NCT00781391) trial.

The results of this study were previously presented at the 2009 International Society on Thrombosis and Haemostasis, July 2009, Boston, Massachusetts, USA.

Keywords

Edoxaban - factor Xa inhibitor - atrial fibrillation - population pharmacokinetics

Note: Dr. Bocanegra is now with POZEN Inc., Chapel Hill, NC, USA; Dr. Rohatagi is now with Piramal Life Sciences Ltd, Mumbai, India; Dr. Zhou is now with Cel-gene Cellular Therapeutics, Warren, NJ, USA.

• References

• 1 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; 06: 1542-1549.
• 2 Zafar MU, Vorchheimer DA, Gaztanaga J. et al. Antithrombotic effects of factor Xa inhibition with DU-176b: Phase-I study of an oral, direct factor Xa inhibitor using an ex-vivo flow chamber. Thromb Haemost 2007; 98: 883-888.
• 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; 08: 2458-2468.
• 4 Raskob G, Cohen AT, Eriksson BI. et al. Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement. A randomized double-blind dose-response study. Thromb Haemost 2010; 104: 642-649.
• 5 Weitz JI, Connolly SJ, Patel I. et al. Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb Haemost 2010; 104: 633-641.
• 6 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.
• 7 Chung N, Jeon HK, Lien LM. et al. Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with non-valvular atrial fibrillation. Thromb Haemost 2011; 105: 535-544.
• 8 Ansell J, Hirsh J, Hylek E. et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 160S-198S.
• 9 Furugohri T, Sugiyama N, Morishima Y. et al. Antithrombin-independent thrombin inhibitors, but not direct factor Xa inhibitors, enhance thrombin generation in plasma through inhibition of thrombin-thrombomodulin-protein C system. Thromb Haemost 2011; 106: 1076-1083.
• 10 Weitz JI. New oral anticoagulants in development. Thromb Haemost 2010; 103: 62-70.
• 11 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.
• 12 Matsushima N, Lee F, Sato T. et al. Absolute bioavailability of edoxaban in healthy subjects. Poster presented at American Association of Pharmaceutical Scientists Annual Meeting and Exposition; 2011. October 23-27, 2011 Washington, DC, USA.:
• 13 Bathala M, Masumoto H, Oguma T. et al. Biotransformation of edoxaban after oral administration to humans. AAPS J. 2010 12. (Suppl 2): AAPS J 2010; 12 (Suppl 2): Abstract W4264.
• 14 Masumoto H, Yoshigae Y, Watanabe K. et al. In vitro metabolism of edoxaban and the enzymes involved in the oxidative metabolism of edoxaban. AAPS J. 2010 12. (Suppl 2): Abstract W4308.
• 15 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 03: 692-694.
• 16 Oguma T, Masumoto H, Yoshigae Y. et al. LC-MS/MS bioanalytical method for the determination of edoxaban in human plasma. Paper presented at Pharmaceutical Sciences World Congress; 2010. November 18, 2010 New Orleans, LA, USA:
• 17 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31-41.
• 18 Turnblad 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 Gage BF, van Walraven C, Pearce L. et al. Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin. Circulation 2004; 19: 2287-2292.
• 20 Bradley JS, Garonzik SM, Forrest A. et al. Pharmacokinetics, pharmacodynamics, and Monte Carlo simulation: selecting the best antimicrobial dose to treat an infection. Pediatr Infect Dis J 2010; 29: 1043-1046.
• 21 Mega JL, Braunwald E, Mohanavelu S. et al. ATLAS ACS-TIMI 46 study group. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009; 374: 29-38.
• 22 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.
• 23 Steg PG, Mehta SR, Jukema JW. et al. RUBY-1 Investigators. RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome. Eur Heart J 2011; 32: 2541-2554.
• 24 Ridout G, de la Motte S, Sramek P. et al. Effect of renal function on edoxaban pharmacokinetics and on population PK/PKD model. Paper presented at: American College of Clinical Pharmacology, ACCP 38th Annual Meeting; September 14 2009. Orlando, FL, USA:
• 25 Yasaka M, Inoue H, Kawai Y. et al. Randomized, parallel group, warfarin control, multicenter phase II study evaluating safety of edoxaban in Japanese subjects with non-valvular atrial fibrillation (NVAF). Poster presented at XXII Congress of International Society on Thrombosis and Haemostasis; July 11-16, 2009 Boston, MA, USA.:
• 26 Sheiner LB. Learning versus confirming in clinical drug development. Clin Pharmacol Ther 1997; 61: 275-291.
• 27 Lalonde RL, Kowalski KG, Hutmacher MM. et al. Model-based drug development. Clin Pharmacol Ther 2007; 82: 21-32.
• 28 Gobburu JV, Lesko LJ. Quantitative disease, drug, and trial models. Annu Rev Pharmacol Toxicol 2009; 49: 291-301.