title: Comparison of calibrated chromogenic anti-Xa assay and PT tests with LC-MS/MS for the therapeutic monitoring of patients treated with rivaroxaban.
abstract: Possibilities to monitor rivaroxaban therapy could be useful in certain circumstances. Prothrombin time (PT) or chromogenic anti-Xa assays such as the Biophen Direct Factor Xa Inhibitor® (DiXaI) have been proposed to estimate rivaroxaban concentrations but are mainly based on in vitro studies. The study aim was to compare PT and Biophen DiXaI® measurements with liquid chromatography-tandem mass spectrometry (LC-MS/MS) measurements in plasma samples from patients treated with Xarelto®. Fifty-two plasma samples were included. PT was performed using Innovin® and Triniclot PT Excel S®. Biophen DiXaI® was performed according to instructions from the manufacturer. The rivaroxaban plasma concentration ranged between 0 and 485 ng/ml as measured by LC-MS/MS. The limits of quantification were 30 ng/ml and 5 ng/ml for Biophen DiXaI® and LC-MS/MS, respectively. The linear correlation between Biophen DiXaI® and LC-MS/MS analyses was high for all rivaroxaban concentrations (r² = 0.95). For concentrations ≤100 ng/ml, r²-value was 0.83. The Bland-Altman analysis showed a mean difference of -16 ng/ml (SD: 25 ng/ml). The PT methods did not correlate well with plasma concentrations measured by LC-MS/MS (r² ≈ 0.60). In conclusion, the important inter-individual variability and the poor correlation with LC-MS/MS preclude the use of PT to estimate rivaroxaban concentrations. Thanks to its small inter-individual variability and good agreement with LC-MS/MS measurements, we recommend the use of Biophen DiXaI® assays to estimate concentrations of rivaroxaban >30 ng/ml. Quantification of low rivaroxaban levels (<30 ng/ml) requires the LC-MS/MS method.
authors.affiliation: Jonathan Douxfils, Department of Pharmacy, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for LIfe Sciences (NARILIS), University of Namur, B-5000, Belgium, E-mail: jonathan.douxfils@unamur.be.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Douxfils
authors.forename: Anne
authors.initials: A
authors.lastname: Tamigniau
authors.forename: Bernard
authors.initials: B
authors.lastname: Chatelain
authors.forename: Christian
authors.initials: C
authors.lastname: Chatelain
authors.forename: Pierre
authors.initials: P
authors.lastname: Wallemacq
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dogné
authors.forename: François
authors.initials: F
authors.lastname: Mullier
mesh_terms: D002138:Calibration; D002853:Chromatography, Liquid; D002863:Chromogenic Compounds / Q000378:metabolism; D065427:Factor Xa Inhibitors; D006801:Humans; D008991:Monitoring, Physiologic / Q000295:instrumentation / Q000379:methods*; D009025:Morpholines / Q000008:administration & dosage / Q000097:blood*; D011517:Prothrombin Time; D015203:Reproducibility of Results; D000069552:Rivaroxaban; D053719:Tandem Mass Spectrometry; D013876:Thiophenes / Q000008:administration & dosage / Q000097:blood*
chemical_list: D002863:Chromogenic Compounds; D065427:Factor Xa Inhibitors; D009025:Morpholines; D013876:Thiophenes; D000069552:Rivaroxaban
keywords: LC-MS/MS; Rivaroxaban; chromogenic anti-Xa assay; monitoring; prothrombin time