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Comparison of a Validated UHPLC-MS/MS Method and Chromogenic Anti-Xa Assays from Different Manufacturer for the Assessment of Edoxaban and its M4 Metabolite Levels in Plasma

1University of Namur, Department of Pharmacy, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for LIfe Sciences (NARILIS), Namur, Belgium, 2QUALIblood s.a., Namur, Belgium, 3Namur Biobank-eXchange (NAB-X), University of Namur, Namur, Belgium, 4Université catholique de Louvain, CHU UCL Namur, Hematology Laboratory, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for Life Sciences (NARILIS), Yvoir, Belgium, 5Université catholique de Louvain, CHU UCL Namurb, Department of Anesthesiology, Namur Thrombosis and Haemostasis Center (NTHC), Yvoir, Belgium, 6Saint-Luc University Hospital, Université catholique de Louvain, Department of Internal Medicine and Infectious Diseases, Brussels, Belgium, 7University of Namur, Department of Pharmacy, Namur Nanosafety Center (NNC), Namur Research Institute for Life Sciences (NARILIS), Namur, Belgium

Abstract Number: PB0165

Meeting: ISTH 2020 Congress

Theme: Coagulation and Natural Anticoagulants » Coagulation Factors and Inhibitors

Background: Currently, chromogenic anti-Xa assays are considered as the most appropriate assays to estimate the concentration of factor Xa inhibitors. Among them, edoxaban is the only compound for which some of the metabolites are reported to be pharmacologically actives. Although generally found at low concentrations, these metabolites could potentially interfere with chromogenic assays.

Aims: To assess the performance of several commercial chromogenic anti-Xa assays with a validated ultra-high-performance-liquid chromatography coupled with a tandem mass spectrometry (UHPLC-MS/MS) method measuring edoxaban and its major active metabolite (edoxaban-M4).

Methods: Measurements of edoxaban were performed on patient samples (n=27) with three chromogenic assays (STA®Liquid Anti-Xa, Biophen Heparin LRT® (High and Low) and Biophen DiXaI® (High and Low)) and compared with a validated UHPLC-MS/MS method assessing concentrations of edoxaban and edoxaban-M4. Spearman’s rank correlation coefficient and Bland-Altman plot were used to compare methodologies.

Results: Spearman correlations showed high correlations between chromogenic assays and UHPLC-MS/MS edoxaban measurements (r ranging from 0.94 (Biophen DiXaI®Low) to 0.98 (STA®Liquid Anti-Xa and Biophen Heparin LRT®). Correlations are improved by adding edoxaban-M4 measures to edoxaban. The participation of M6- and M8-metabolite may partly explain this discrepancy. Bland-Altman plots show that chromogenic assays calibrated with edoxaban underestimate edoxaban concentrations when compared with UHPLC-MS/MS measurement. Linear regressions show a tendency to underestimate edoxaban concentrations, especially at higher concentrations (►Figure 1).


[Figure 1: Bland-Altman plot for chromogenic assays and UHPLC-MS/MS: Involvement of edoxaban-M4 metabolite.]

Conclusions: Calibrations involving concomitantly edoxaban and active metabolites should be preferred. This will to avoid, especially in case of drug-drug interactions (e.g. P450 cytochrome or transporters inducers), a risk of inadequate control of coagulation, due to different contribution of the metabolites to the total anti-Xa activity which serves for the estimation of edoxaban concentration. Further investigations are needed to evaluate the impact of edoxaban and its active metabolite, edoxaban-M4, on chromogenic assays on a larger sampling.

To cite this abstract in AMA style:

Siriez R, Bouvy C, Dogné J-, Hardy M, Hainaut P, Laloy J, Mullier F, Yildiz H, Douxfils J. Comparison of a Validated UHPLC-MS/MS Method and Chromogenic Anti-Xa Assays from Different Manufacturer for the Assessment of Edoxaban and its M4 Metabolite Levels in Plasma [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/comparison-of-a-validated-uhplc-ms-ms-method-and-chromogenic-anti-xa-assays-from-different-manufacturer-for-the-assessment-of-edoxaban-and-its-m4-metabolite-levels-in-plasma/. Accessed September 22, 2023.

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