Importance of measuring pharmacologically active metabolites of edoxaban: development and validation of an ultra-high-performance liquid chromatography coupled with a tandem mass spectrometry method

Romain Siriez, Lütfiye Alpan, Kossay Elasaad, Philippe Devel, Julie Laloy, Jean-Michel Dogne, Jonathan Douxfils

Résultats de recherche: Contribution à un journal/une revueArticle

Résumé

Although DOACs do not require regular measurements of their blood concentrations, clinical situations may require an assessment of their concentration. Among the factor Xa inhibitors, edoxaban is the only compound for which some metabolites (e.g. edoxaban-M4) are reported to be pharmacologically active. Therefore, their contribution could interfere with assays used for the estimation of edoxaban concentration. In addition, drug interactions may alter the metabolite/parent compound ratio making the sole estimation of edoxaban concentration, a poor assessment of the overall anticoagulation. To develop a validated UHPLC-MS/MS method to quantify simultaneously edoxaban and its more relevant M4-metabolite in human plasma. Electrospray ionization and chromatographic separation were optimized for the simultaneous dosage of edoxaban and edoxaban-M4. The method was validated according to regulatory guidelines for bioanalytical method validation. The total run time was 6 min. The method was validated for calibration curves, precision, accuracy, carry-over, selectivity, matrix effect and short-time stability. This method permits quantification of edoxaban and edoxaban-M4 providing complementary information about the inhibitory effect of this active metabolite in chronometric or chromogenic assays. Although patients treated with edoxaban exhibits usually low concentrations of active metabolites, the measurement of edoxaban-M4 is interesting; especially in case of drug interactions. Indeed, concomitant prescriptions of edoxaban and carbamazepine or rifampicin is frequent and may lead to disturbance of the estimations of edoxaban concentration by chromogenic anti-Xa assays. Therefore, patients are at risk of having inadequate control of anticoagulation supporting the need of measuring the most representative edoxaban metabolite concomitantly to the parent compound.

langue originaleAnglais
Nombre de pages33
journalJournal of Thrombosis and Thrombolysis
Date de mise en ligne précoce2020
Les DOIs
étatPublié - 2020

Empreinte digitale

Tandem Mass Spectrometry
High Pressure Liquid Chromatography
edoxaban
Drug Interactions
Carbamazepine
Rifampin
Calibration
Prescriptions

mots-clés

  • Edoxaban
  • Edoxaban-M4
  • Ultra-High-Performance Liquid Chromatography/tandem mass spectrometry
  • Metabolite
  • Direct Oral Anticoagulant

Citer ceci

@article{be661d45f8d6421e92dd3420b3e9536d,
title = "Importance of measuring pharmacologically active metabolites of edoxaban: development and validation of an ultra-high-performance liquid chromatography coupled with a tandem mass spectrometry method",
abstract = "Although DOACs do not require regular measurements of their blood concentrations, clinical situations may require an assessment of their concentration. Among the factor Xa inhibitors, edoxaban is the only compound for which some metabolites (e.g. edoxaban-M4) are reported to be pharmacologically active. Therefore, their contribution could interfere with assays used for the estimation of edoxaban concentration. In addition, drug interactions may alter the metabolite/parent compound ratio making the sole estimation of edoxaban concentration, a poor assessment of the overall anticoagulation. To develop a validated UHPLC-MS/MS method to quantify simultaneously edoxaban and its more relevant M4-metabolite in human plasma. Electrospray ionization and chromatographic separation were optimized for the simultaneous dosage of edoxaban and edoxaban-M4. The method was validated according to regulatory guidelines for bioanalytical method validation. The total run time was 6 min. The method was validated for calibration curves, precision, accuracy, carry-over, selectivity, matrix effect and short-time stability. This method permits quantification of edoxaban and edoxaban-M4 providing complementary information about the inhibitory effect of this active metabolite in chronometric or chromogenic assays. Although patients treated with edoxaban exhibits usually low concentrations of active metabolites, the measurement of edoxaban-M4 is interesting; especially in case of drug interactions. Indeed, concomitant prescriptions of edoxaban and carbamazepine or rifampicin is frequent and may lead to disturbance of the estimations of edoxaban concentration by chromogenic anti-Xa assays. Therefore, patients are at risk of having inadequate control of anticoagulation supporting the need of measuring the most representative edoxaban metabolite concomitantly to the parent compound.",
keywords = "Edoxaban, Edoxaban-M4, Ultra-High-Performance Liquid Chromatography/tandem mass spectrometry, Metabolite, Direct Oral Anticoagulant",
author = "Romain Siriez and L{\"u}tfiye Alpan and Kossay Elasaad and Philippe Devel and Julie Laloy and Jean-Michel Dogne and Jonathan Douxfils",
year = "2020",
doi = "10.1007/s11239-019-02030-5",
language = "English",
journal = "Journal of Thrombosis and Thrombolysis",
issn = "0929-5305",
publisher = "Springer New York",

}

TY - JOUR

T1 - Importance of measuring pharmacologically active metabolites of edoxaban

T2 - development and validation of an ultra-high-performance liquid chromatography coupled with a tandem mass spectrometry method

AU - Siriez, Romain

AU - Alpan, Lütfiye

AU - Elasaad, Kossay

AU - Devel, Philippe

AU - Laloy, Julie

AU - Dogne, Jean-Michel

AU - Douxfils, Jonathan

PY - 2020

Y1 - 2020

N2 - Although DOACs do not require regular measurements of their blood concentrations, clinical situations may require an assessment of their concentration. Among the factor Xa inhibitors, edoxaban is the only compound for which some metabolites (e.g. edoxaban-M4) are reported to be pharmacologically active. Therefore, their contribution could interfere with assays used for the estimation of edoxaban concentration. In addition, drug interactions may alter the metabolite/parent compound ratio making the sole estimation of edoxaban concentration, a poor assessment of the overall anticoagulation. To develop a validated UHPLC-MS/MS method to quantify simultaneously edoxaban and its more relevant M4-metabolite in human plasma. Electrospray ionization and chromatographic separation were optimized for the simultaneous dosage of edoxaban and edoxaban-M4. The method was validated according to regulatory guidelines for bioanalytical method validation. The total run time was 6 min. The method was validated for calibration curves, precision, accuracy, carry-over, selectivity, matrix effect and short-time stability. This method permits quantification of edoxaban and edoxaban-M4 providing complementary information about the inhibitory effect of this active metabolite in chronometric or chromogenic assays. Although patients treated with edoxaban exhibits usually low concentrations of active metabolites, the measurement of edoxaban-M4 is interesting; especially in case of drug interactions. Indeed, concomitant prescriptions of edoxaban and carbamazepine or rifampicin is frequent and may lead to disturbance of the estimations of edoxaban concentration by chromogenic anti-Xa assays. Therefore, patients are at risk of having inadequate control of anticoagulation supporting the need of measuring the most representative edoxaban metabolite concomitantly to the parent compound.

AB - Although DOACs do not require regular measurements of their blood concentrations, clinical situations may require an assessment of their concentration. Among the factor Xa inhibitors, edoxaban is the only compound for which some metabolites (e.g. edoxaban-M4) are reported to be pharmacologically active. Therefore, their contribution could interfere with assays used for the estimation of edoxaban concentration. In addition, drug interactions may alter the metabolite/parent compound ratio making the sole estimation of edoxaban concentration, a poor assessment of the overall anticoagulation. To develop a validated UHPLC-MS/MS method to quantify simultaneously edoxaban and its more relevant M4-metabolite in human plasma. Electrospray ionization and chromatographic separation were optimized for the simultaneous dosage of edoxaban and edoxaban-M4. The method was validated according to regulatory guidelines for bioanalytical method validation. The total run time was 6 min. The method was validated for calibration curves, precision, accuracy, carry-over, selectivity, matrix effect and short-time stability. This method permits quantification of edoxaban and edoxaban-M4 providing complementary information about the inhibitory effect of this active metabolite in chronometric or chromogenic assays. Although patients treated with edoxaban exhibits usually low concentrations of active metabolites, the measurement of edoxaban-M4 is interesting; especially in case of drug interactions. Indeed, concomitant prescriptions of edoxaban and carbamazepine or rifampicin is frequent and may lead to disturbance of the estimations of edoxaban concentration by chromogenic anti-Xa assays. Therefore, patients are at risk of having inadequate control of anticoagulation supporting the need of measuring the most representative edoxaban metabolite concomitantly to the parent compound.

KW - Edoxaban

KW - Edoxaban-M4

KW - Ultra-High-Performance Liquid Chromatography/tandem mass spectrometry

KW - Metabolite

KW - Direct Oral Anticoagulant

UR - http://www.mendeley.com/catalogue/importance-measuring-pharmacologically-active-metabolites-edoxaban-development-validation-ultrahighp

UR - http://www.scopus.com/inward/record.url?scp=85077674561&partnerID=8YFLogxK

U2 - 10.1007/s11239-019-02030-5

DO - 10.1007/s11239-019-02030-5

M3 - Article

C2 - 31925664

JO - Journal of Thrombosis and Thrombolysis

JF - Journal of Thrombosis and Thrombolysis

SN - 0929-5305

ER -