Pharmacokinetics, Biotransformation, and Mass Balance of Edoxaban, a Selective, Direct Factor Xa Inhibitor, in Humans

Abstract

ABSTRACT:This study determined the mass balance and pharmacokinetics of edoxaban in humans after oral administration of [ 14 C]edoxaban.After oral administration of 60 mg (as active moiety) of [ 14 C]edoxaban to six healthy male subjects, serial blood/plasma and urinary and fecal samples were collected for up to 168 h postdose. All samples were analyzed for total radioactivity by liquid scintillation counting and for concentrations of edoxaban and four metabolites in plasma, urine, and fecal samples by either high-performance liquid chromatography/tandem mass spectrometry method using multiple reaction modes, or a liquid chromatography radiometric method. The mean recovery of radioactivity was >97% of the administered radioactive dose, with 62.2% eliminated in feces and 35.4% in urine. Unchanged edoxaban accounted for the majority of radioactivity, with 49.1 and 23.8% of the dose as parent observed in feces and urine, respectively. Unchanged edoxaban was the most abundant species in plasma, with a mean area under the curve (AUC) 0؊ؕ of 1596 ng ⅐ h/ml. The next most abundant species was metabolite M4, with a mean AUC 0؊ؕ 147 ng ⅐ h/ml. The mass balance of edoxaban was well described, with unchanged edoxaban as the most abundant component of total radioactivity. Edoxaban is eliminated through multiple pathways, but each accounts for only a small amount of overall elimination.

Determination of Edoxaban in Bulk and in Tablet Dosage Form by Stability Indicating High-Performance Liquid Chromatography

“…4,5 So far EXN is not official in any pharmacopeias. The literature is poor regarding the reports on the assay of EXN.…”

Edoxaban

“…The conversion of prothrombin (factor II) to thrombin (factor IIa) is mediated by factor Xa, which catalyzes the formation of a fibrin clot via conversion of prothrombin to thrombin, ultimately leading to thrombus formation and clotting. 15,[17][18][19] By inhibiting factor Xa, edoxaban is able to block the final stages of the coagulation cascade. Edoxaban is selective for factor Xa and inhibits downstream clotting factors, such as factor IIa and fibrin, while factors XIIa, XIa, IXa, or VIIa are unaffected.…”

“…The drug is primarily metabolized via hydrolysis (approximately 25% total dose), with approximately one-third eliminated renally and two-thirds eliminated hepatically. 1,17,23 Unchanged edoxaban elimination in the urine accounts for 50% of the drug's total clearance. 1, 17 Edoxaban is minimally metabolized by cytochrome P450 (CYP-450) enzymes, although it is a substrate of the human efflux transporter P-glycoprotein (P-gp).…”

Edoxaban Exposure‐Response Analysis and Clinical Utility Index Assessment in Patients With Symptomatic Deep‐Vein Thrombosis or Pulmonary Embolism

“…Plasma protein binding of edoxaban is relatively low, ranging from 40–59% 6. Edoxaban is eliminated via both renal excretion and liver metabolism pathways, with ∼50% of systemically absorbed drug excreted in urine 6.…”

“…Plasma protein binding of edoxaban is relatively low, ranging from 40–59% 6. Edoxaban is eliminated via both renal excretion and liver metabolism pathways, with ∼50% of systemically absorbed drug excreted in urine 6. It is a P‐glycoprotein (P‐gp) substrate; hence, significant drug‐drug interactions are expected when edoxaban is used concurrently with strong P‐gp inhibitors 7, 8…”