Mika Skeppholm1, Fadiea Al-Aieshy2, Maria Berndtsson3, Faris Al-Khalili4, Yuko Rönquist-Nii5, Lisbeth Söderblom3, Annika Y Östlund5, Anton Pohanka5, Jovan Antovic3, Rickard E Malmström2. 1. Department of Medicine Solna, Karolinska Institutet & Department of Cardiology, Danderyd Hospital, Stockholm, Sweden. Electronic address: mika.skeppholm@ds.se. 2. Department of Medicine Solna, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden. 3. Department of Coagulation Research, Institute for Molecular Medicine and Surgery, Karolinska Institutet, & Department of Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden. 4. Department of Clinical Sciences, Cardiology Unit, Karolinska Institutet, Danderyd's Hospital, and Stockholm Heart Center, Stockholm, Sweden. 5. Department of Laboratory Medicine Huddinge, Clinical Pharmacology Unit, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
Abstract
INTRODUCTION: The direct factor-Xa inhibitor apixaban is approved e.g. for the prevention of stroke in patients with atrial fibrillation (AF). Although routine monitoring of apixaban therapy is currently not recommended, selective monitoring could be useful to optimize efficacy and safety in certain clinical situations. We studied the exposure and effect of apixaban using different laboratory methods in a clinical setting with a well-defined cohort of AF patients. MATERIAL AND METHODS: Seventy AF patients (72±7.4years, 64 % men, mean CHADS2 score 1.7) treated with apixaban 2.5 (n=10) or 5mg BID (n=60). Trough plasma apixaban concentrations determined by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) were compared to the coagulation assays Anti-factor Xa, PT-INR and aPTT. RESULTS: The apixaban plasma concentration determined by LC-MS/MS varied more than 10-fold overall. The range was between 15-83 and 29-186ng/mL for the 2.5mg BID and 5mg BID respectively, with patients receiving 5mg BID having significantly higher apixaban concentrations (p<0.001). A strong correlation between LC-MS/MS and anti-FXa-assay was found (p<0.001), while aPTT and PT-INR were not sensitive enough. There were no significant correlations between gender, creatinine clearance, body weight or age and apixaban exposure. CONCLUSIONS: Anti-FXa-assay performed well upon apixaban concentrations in a normal exposure range. Still LC-MS/MS remains the "gold standard" method, covering also low concentrations. Compared to clinical trials, we observed relatively lower apixaban exposure and a more pronounced difference between high and low dose. Additional information regarding apixaban exposure and benefit-risk profile is needed in order to individualize treatment.
INTRODUCTION: The direct factor-Xa inhibitor apixaban is approved e.g. for the prevention of stroke in patients with atrial fibrillation (AF). Although routine monitoring of apixaban therapy is currently not recommended, selective monitoring could be useful to optimize efficacy and safety in certain clinical situations. We studied the exposure and effect of apixaban using different laboratory methods in a clinical setting with a well-defined cohort of AFpatients. MATERIAL AND METHODS: Seventy AFpatients (72±7.4years, 64 % men, mean CHADS2 score 1.7) treated with apixaban 2.5 (n=10) or 5mg BID (n=60). Trough plasma apixaban concentrations determined by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) were compared to the coagulation assays Anti-factor Xa, PT-INR and aPTT. RESULTS: The apixaban plasma concentration determined by LC-MS/MS varied more than 10-fold overall. The range was between 15-83 and 29-186ng/mL for the 2.5mg BID and 5mg BID respectively, with patients receiving 5mg BID having significantly higher apixaban concentrations (p<0.001). A strong correlation between LC-MS/MS and anti-FXa-assay was found (p<0.001), while aPTT and PT-INR were not sensitive enough. There were no significant correlations between gender, creatinine clearance, body weight or age and apixaban exposure. CONCLUSIONS: Anti-FXa-assay performed well upon apixaban concentrations in a normal exposure range. Still LC-MS/MS remains the "gold standard" method, covering also low concentrations. Compared to clinical trials, we observed relatively lower apixaban exposure and a more pronounced difference between high and low dose. Additional information regarding apixaban exposure and benefit-risk profile is needed in order to individualize treatment.
Authors: H M H Spronk; T Padro; J E Siland; J H Prochaska; J Winters; A C van der Wal; J J Posthuma; G Lowe; E d'Alessandro; P Wenzel; D M Coenen; P H Reitsma; W Ruf; R H van Gorp; R R Koenen; T Vajen; N A Alshaikh; A S Wolberg; F L Macrae; N Asquith; J Heemskerk; A Heinzmann; M Moorlag; N Mackman; P van der Meijden; J C M Meijers; M Heestermans; T Renné; S Dólleman; W Chayouâ; R A S Ariëns; C C Baaten; M Nagy; A Kuliopulos; J J Posma; P Harrison; M J Vries; H J G M Crijns; E A M P Dudink; H R Buller; Y M C Henskens; A Själander; S Zwaveling; O Erküner; J W Eikelboom; A Gulpen; F E C M Peeters; J Douxfils; R H Olie; T Baglin; A Leader; U Schotten; B Scaf; H M M van Beusekom; L O Mosnier; L van der Vorm; P Declerck; M Visser; D W J Dippel; V J Strijbis; K Pertiwi; A J Ten Cate-Hoek; H Ten Cate Journal: Thromb Haemost Date: 2018-01-29 Impact factor: 5.249
Authors: Fadiea Al-Aieshy; Rickard E Malmström; Jovan Antovic; Anton Pohanka; Yuko Rönquist-Nii; Maria Berndtsson; Faris Al-Khalili; Mika Skeppholm Journal: Eur J Clin Pharmacol Date: 2016-04-11 Impact factor: 2.953