title: Clinical evaluation of laboratory methods to monitor exposure of rivaroxaban at trough and peak in patients with atrial fibrillation.
abstract: OBJECTIVE
  The one-dose daily regime of rivaroxaban could cause a pronounced variability in concentration and effect of which a deeper knowledge is warranted. This study aimed to evaluate the typical exposure range and effect of the direct factor Xa (FXa)-inhibitor rivaroxaban in a cohort of well-characterized patients with atrial fibrillation (AF).
  
  
  METHODS
  Seventy-one AF patients (72 ± 8 years, 55 % men) were treated with rivaroxaban 15 mg/20 mg (n = 10/61) OD. Trough (n = 71) and peak (n = 30) plasma concentrations determined by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) were compared to the coagulation assays anti-FXa for rivaroxaban, prothrombin time-international normalized ratio (PT-INR) (venous samples and point-of-care assay (POC) CoaguChek XS Pro), and aPTT.
  
  
  RESULTS
  Median rivaroxaban plasma concentrations by LC-MS/MS were 34 (range 5-84) and 233 ng/ml (range 120-375) at trough and peak, respectively. A strong correlation between LC-MS/MS and the anti-FXa assay was found (p < 0.001) for both trough (r (2) = 0.92) and peak (r (2) = 0.91) samples. PT-INR results from the POC assay, but not from the conventional PT assay, correlated significantly with LC-MS/MS in peak samples exclusively (r (2) = 0.41, p < 0.001).
  
  
  CONCLUSIONS
  In "real-life" AF patients treated with rivaroxaban, we observed a pronounced variability in plasma concentrations at trough and to a lesser extent at peak measured by LC-MS/MS. The anti-FXa assay performed well upon rivaroxaban levels in a normal exposure range, although LC-MS/MS remains the only method that covers the whole concentration range with accuracy. Interestingly, the POC assay for PT-INR could be useful to indicate high exposure to rivaroxaban in emergency situations although further validation is required.
authors.affiliation: Department of Medicine Solna, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden. fadiea.al-aieshy@karolinska.se.|Clinical Pharmacology, Drug Safety and Evaluation Sector, L7:03, Karolinska University Hospital Solna, -17176, Stockholm, SE, Sweden. fadiea.al-aieshy@karolinska.se.
authors.forename: Fadiea
authors.initials: F
authors.lastname: Al-Aieshy
authors.affiliation: Department of Medicine Solna, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Rickard E
authors.initials: RE
authors.lastname: Malmström
authors.affiliation: Department of Coagulation Research, Institute for Molecular Medicine and Surgery, Karolinska Institutet & Department of Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Jovan
authors.initials: J
authors.lastname: Antovic
authors.affiliation: Department of Laboratory Medicine Huddinge, Division of Clinical Pharmacology, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Anton
authors.initials: A
authors.lastname: Pohanka
authors.affiliation: Department of Laboratory Medicine Huddinge, Division of Clinical Pharmacology, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Rönquist-Nii
authors.affiliation: Department of Coagulation Research, Institute for Molecular Medicine and Surgery, Karolinska Institutet & Department of Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Berndtsson
authors.affiliation: Department of Clinical Sciences, Cardiology Unit, Karolinska Institutet, Danderyds Hospital, Stockholm Heart Center, Stockholm, Sweden.
authors.forename: Faris
authors.initials: F
authors.lastname: Al-Khalili
authors.affiliation: Department of Medicine Solna, Karolinska Institutet & Department of Cardiology, Danderyds Hospital, Stockholm, Sweden.
authors.forename: Mika
authors.initials: M
authors.lastname: Skeppholm
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation / Q000097:blood* / Q000188:drug therapy; D002853:Chromatography, Liquid; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D000069552:Rivaroxaban / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D053719:Tandem Mass Spectrometry
chemical_list: D065427:Factor Xa Inhibitors; D000069552:Rivaroxaban; D015951:Factor Xa
keywords: Anti-FXa-assay; LC-MS/MS; NOAC; POC-assay; Rivaroxaban; Therapeutic drug monitoring