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Drug Interactions in Edoxaban Treated Patients: A Pilot Study Revealing the Changes of the Metabolite to Parent Ratio and its Potential Clinical Importance

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

Abstract Number: PB0164

Meeting: ISTH 2020 Congress

Theme: Coagulation and Natural Anticoagulants » Coagulation Factors and Inhibitors

Background: Among the factor Xa inhibitors, edoxaban is the only compound for which some of the metabolites (edoxaban-M4, -M6 and -M8 metabolites) are reported to be pharmacologically actives. These metabolites could potentially interfere with chromogenic assays usually used for the estimation of edoxaban concentrations. Edoxaban has usually low concentrations of active metabolites, which do not impact the anticoagulant activity. However, in presence of drug interactions, the levels of edoxaban-M4 may contribute significantly to factor Xa inhibition.

Aims: To evaluate the impact of rifampicin and carbamazepine on edoxaban-M4/edoxaban ratio measurements in patients.

Methods: Measurements of edoxaban were performed with chromogenic assay (STA® Liquid Anti-Xa) and compared with a validated ultra-high-performance-liquid-chromatography coupled with a tandem mass spectrometry (UHPLC-MS/MS) method assessing concentrations of edoxaban and edoxaban-M4. Patients with drug-drug interactions (n=14) were compared with a group without interaction (n=79).

Results: Mann-Whitney test reports significative difference of edoxaban-M4/edoxaban ratio (p=0.0152) between patients’ group with drugs interactions and without interaction (►Figure 1).


[Figure 1: Density distribution of edoxaban-M4/edoxaban ratios for patients with and without interaction.]

This difference is more important at Cthrough (p=0.0017) and not significant at Cmax. Wilcoxon test showed a significant difference from the theoretical edoxaban-M4/edoxaban ratio of 10% at Cthrough (p=0.0156) but not at Cmax. However, one patient with renal insufficiency accumulates edoxaban-M4 to higher levels. Finally, Spearman correlations showed significant difference for correlation between chromogenic assay and UHPLC-MS/MS edoxaban measurements for interactions group (r=0.87) than for group without interaction (r=0.98). Bland-Altman and Spearman correlations for the interaction group is improved by taking into account edoxaban-M4 (r=0.96) (►Figure 2).


[Figure 2: Method comparison between chromogenic anti-Xa assay and UHPLC-MS/MS measurements.]

Induction of other metabolites, in particular edoxaban-M6, may explain this discrepancy.

Conclusions: Drug-drug interactions may increase edoxaban-M4/edoxaban ratio leading to a higher risk of inadequate control of coagulation. These results support the need to measure metabolites concomitantly to edoxaban. Further investigations are needed to assess the pharmacokinetic impact of interaction on a larger population.

To cite this abstract in AMA style:

Siriez R, Dogné J-, Douxfils J, Hardy M, Laloy J, Mullier F, Yildiz H, Hainaut P. Drug Interactions in Edoxaban Treated Patients: A Pilot Study Revealing the Changes of the Metabolite to Parent Ratio and its Potential Clinical Importance [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/drug-interactions-in-edoxaban-treated-patients-a-pilot-study-revealing-the-changes-of-the-metabolite-to-parent-ratio-and-its-potential-clinical-importance/. Accessed September 29, 2023.

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