Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis

Summary

Edoxaban is an oral, direct, once-daily, factor Xa inhibitor developed for stroke prevention in patients with atrial fibrillation and for the treatment and secondary prevention of recurrent thromboembolism in patients with acute symptomatic venous thromboembolism. Among elderly patients who require anticoagulation therapies, some may have end-stage renal disease (ESRD). This open-label, phase 1, randomised, two-way crossover study was conducted to evaluate the pharmacokinetics of edoxaban in 10 subjects on haemodialysis. Eligible subjects with ESRD on chronic haemodialysis received a single, oraldose of edoxaban 15 mg 2 hours (h) prior to (on-dialysis) or in between (off-dialysis) haemodialysis sessions. Haemodialysis resulted in a minor decrease in mean total exposure (AUC_0-∞; 676.2 ng⋅h/ml) as compared with that observed in subjects off-dialysis (691.7 ng⋅h/ml). Mean maximum observed plasma concentration (C_max) values were comparable between on-dialysis and off-dialysis treatments (53.3 vs 56.3 ng/ml, respectively). Mean apparent total body clearance (CL/F) values were 24.1 and 22.5 l/h during the on-dialysis and off-dialysis treatment periods, respectively. Dialyser clearance was 5.7 l/h and haemodialysis clearance was 6.1 l/h. Haemodialysis clearance was only 6.1 l/h, suggesting that it only accounts for one-fourth of the total clearance in these subjects. A single, oral dose of 15 mg of edoxaban was well tolerated by subjects with ESRD. In conclusion, based on these single-dose PK data, a supplementary dose of edoxaban may not be required following a haemodialysis session. Importantly, haemodialysis is not an effective mechanism for removal of edoxaban from the blood.

Keywords

Edoxaban - haemodialysis - pharmacokinetics - oral factor Xa inhibitor - elimination

• References

• 1 Dreisbach AW, Lertora JJ. The effect of chronic renal failure on drug metabolism and transport. Expert Opin Drug Metab Toxicol 2008; 04: 1065-1074.
• 2 Verbeeck RK, Musuamba FT. Pharmacokinetics and dosage adjustment in patients with renal dysfunction. Eur J Clin Pharmacol 2009; 65: 757-773.
• 3 U. S. Dept of Health and Human Services, Food and Drug Administration, Centre for Drug Evaluation and Research (CDER). Guidance for industry. Pharmacokinetics in patients with impaired renal function - study design, data analysis, and impact on dosing and labeling. Draft guidance. http://www.fda.gov/downloads/Drugs/.../Guidances/UCM204959.pdf Published March 2010 [cited 2013 April 30]
• 4 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.
• 5 Hokusai VTE, Investigators Buller HR, Decousus H. et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369: 1406-1415.
• 6 Giugliano RP, Ruff CT, Braunwald E. et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369: 2093-2104.
• 7 Matsushima N, Lee F, Sato T. et al. Bioavailability and safety of the factor xa inhibitor edoxaban and the effects of quinidine in healthy subjects. Clin Pharm in Drug Dev 2013; 02: 358-366.
• 8 Bathala MS, Masumoto H, Oguma T. et al. Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor xa inhibitor, in humans. Drug Metab Dispos 2012; 40: 2250-2255.
• 9 White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107: I4-I8.
• 10 Marinigh R, Lip GY, Fiotti N. et al. Age as a risk factor for stroke in atrial fibrillation patients: implications for thromboprophylaxis: Implications for thromboprophylaxis. J Am Coll Cardiol 2010; 56: 827-837.
• 11 Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985; 33: 278-285.
• 12 Ridout G, de la Motte S, Niemczyk S. et al. Effect of renal function on edoxaban pharmacokinetics (PK) and on population PK/PD model. J Clin Pharmacol 2009; 49: 1124. Abstract 1144.
• 13 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: 925-936.
• 14 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.