The edoxaban-M4 metabolite and measurement of edoxaban by chromogenic assays in human plasma

Romain Siriez, Halil Yildiz, Céline Bouvy, Hélène Haguet, Vincent Maloteau, Michaël Hardy, François Mullier, Jean-Michel Dogné, Philippe Hainaut, Jonathan Douxfils

Research output: Contribution to journalArticlepeer-review


Introduction: Edoxaban is the only anti-Xa inhibitor metabolized in pharmacologically active moiety that could interfere with chromogenic anti-Xa assays, especially in case of drug-drug interactions or physiological disorders.

Materials and methods: We evaluated the contribution of the main metabolite of edoxaban, edoxaban-M4 (M4), in 79 plasma samples from patients taking edoxaban. The total anti-Xa activity was evaluated on three different chromogenic factor Xa-based assays. Results were compared with a validated ultra-high-performance liquid chromatography coupled with a tandem mass spectrometry measurement. Edoxaban and its active M4 metabolite have also been spiked separately in normal pooled plasma to assess the sensitivity of chromogenic anti-Xa assays to both molecules individually.

Results: Spiked edoxaban or M4 provided different slopes of linear regression models between chromogenic and chromatographic measurement (from 0.97 for STA Liquid Anti-Xa to 1.10 for Biophen Heparin LRT Low with edoxaban and from 0.70 for Biophen DiXaI High to 0.83 for Biophen Heparin LRT High, respectively). A positive correlation is observed between the increase of the ratio M4/edoxaban with the difference between chromogenic and chromatographic measurements.

Conclusion: Edoxaban and M4 do not similarly impact chromogenic assays, leading to biased chromogenic estimations of ponderal concentrations. In patient samples, this impact is even more important at low concentrations or in the case of an increase in the M4/edoxaban ratio because of hepatic or renal impairments or in case of drug interactions. This study highlights the limitations and risks of error of expressing results in ponderal concentrations instead of global activity anti-Xa.

Original languageEnglish
Article numbere12680
Pages (from-to)e12680
JournalResearch and Practice in Thrombosis and Haemostasis
Issue number3
Publication statusPublished - Mar 2022
Externally publishedYes


  • anticoagulants
  • chromatography
  • drug interactions
  • edoxaban
  • high pressure liquid
  • patients


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