Measurement of apixaban, dabigatran, edoxaban and rivaroxaban in human plasma using automated online solid-phase extraction combined with ultra-performance liquid chromatography-tandem mass spectrometry and its comparison with coagulation assays

Kühn, Joachim; Gripp, Tatjana; Flieder, Tobias; Hammerschmidt, Andreas; Hendig, Doris; Faust, Isabel; Knabbe, Cornelius; Birschmann, Ingvíld

doi:10.1016/j.cca.2018.08.017

Cited by 29 publications

(16 citation statements)

References 38 publications

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“…Additionally, at baseline, a full blood count, baseline coagulation tests, inflammatory markers, protein/albumin as well as liver and kidney function tests were performed. Further samples of citrated whole blood were centrifuged at 2500 g for 15 min to yield citrated plasma and stored at our center at − 80°C; one sample per time point was later shipped to the Institute for Laboratory and Transfusion Medicine at the Heart and Diabetes Center of Ruhr University (Bad Oeynhausen, Germany) for ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), which was performed in a manner previously described [14] as a gold-standard method to determine exact edoxaban plasma concentrations. All POCT and laboratory-based tests were performed according to manufacturers' instructions by thoroughly trained investigators and technicians.…”

Section: Coagulation Testingmentioning

confidence: 99%

Point-of-care testing for emergency assessment of coagulation in patients treated with direct oral anticoagulants including edoxaban

Härtig

Birschmann

Hörber

et al. 2021

Neurol. Res. Pract.

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Background Direct oral anticoagulants (DOAC) including edoxaban are increasingly used for stroke prevention in atrial fibrillation. Despite treatment, annual stroke rate in these patients remains 1–2%. Rapid assessment of coagulation would be useful to guide thrombolysis or reversal therapy in this growing population of DOAC/edoxaban-treated stroke patients. Employing the Hemochron™ Signature Elite point-of-care test system (HC-POCT), clinically relevant plasma concentrations of dabigatran and rivaroxaban can be excluded in a blood sample. However, no data exists on the effect of edoxaban on HC-POCT results. We evaluated whether edoxaban plasma concentrations above the current treatment thresholds for thrombolysis or anticoagulation reversal (i.e., 30 and 50 ng/mL) can be ruled out with the HC-POCT. Methods We prospectively studied patients receiving a first dose of edoxaban. Six blood samples were collected from each patient: before, 0.5, 1, 2, 8, and 24 h after drug intake. HC-POCT-based INR (HC-INR), activated clotting time (HC-ACT+ and HC-ACT-LR), activated partial thromboplastin time (HC-aPTT), and mass spectrometry for edoxaban plasma concentrations were performed at each time-point. We calculated correlations, receiver operating characteristics (ROC) and test-specific cut-offs for ruling out edoxaban concentrations > 30 and > 50 ng/mL in a blood sample. Results One hundred twenty blood samples from 20 edoxaban-treated patients were analyzed. Edoxaban plasma concentrations ranged from 0 to 512 ng/mL. HC-INR/HC-ACT+/HC-ACT-LR/HC-aPTT ranged from 0.7–8.3/78–310 s/65–215 s/19–93 s, and Pearson’s correlation coefficients showed moderate to very strong correlations with edoxaban concentrations (r = 0.95/0.79/0.70/0.60). With areas under the ROC curve of 0.997 (95% confidence interval: 0.991–0.971) and 0.989 (0.975–1.000), HC-INR most reliably ruled out edoxaban concentrations > 30 and > 50 ng/mL, respectively, and HC-INR results ≤1.5 and ≤ 2.1 provided specificity/sensitivity of 98.6% (91.2–99.9)/98.0% (88.0–99.9) and 96.8% (88.0–99.4)/96.5% (86.8–99.4). Conclusions Our study represents the first systematic evaluation of the HC-POCT in edoxaban-treated patients. Applying sufficiently low assay-specific cut-offs, the HC-POCT may not only be used to reliably rule out dabigatran and rivaroxaban, but also very low edoxaban concentrations in a blood sample. Because the assay-specific cut-offs were retrospectively defined, further investigation is warranted. Trial registration ClinicalTrials.gov, registration number: NCT02825394, registered on: 07/07/2016, URL

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Section: Coagulation Testingmentioning

confidence: 99%

Point-of-care testing for emergency assessment of coagulation in patients treated with direct oral anticoagulants including edoxaban

Härtig

Birschmann

Hörber

et al. 2021

Neurol. Res. Pract.

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“…Rivaroxaban has been widely used in clinical practice recently, and co‐administration of rivaroxaban with other drugs has become more and more popular than ever. To better evaluate its pharmacokinetic characters, several LC‐MS/MS methods have been developed for the determination of rivaroxaban in human blood samples 30–32 . Recently, one liquid chromatography‐tandem mass spectrometry method for the simultaneous detection of 3 oral anticoagulants, including rivaroxaban, has been reported with the run‐time of 5 min and LOD of 0.025 ng/ml 33 .…”

Section: Discussionmentioning

confidence: 99%

Naringenin has an inhibitory effect on rivaroxaban in rats both in vitro and in vivo

Shi

Zhao

Chen

et al. 2021

Pharmacology Res & Perspec

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Food–drug interactions are reported to have some impacts on the pharmacokinetics and pharmacodynamics of various oral drugs. To better understand the effects of naringenin, one natural product in many fruits, on the pharmacokinetics of rivaroxaban, drug–drug interactions (DDIs) between naringenin and rivaroxaban in vitro were investigated in Sprague–Dawley (SD) rat liver microsomes. For the DDIs in vivo, 12 male SD rats were randomly divided into the experimental group and the control group with six rats in each group. Rats in the experimental group were pre‐treated with naringenin (10 mg/kg/day) for 2 weeks before the administration of rivaroxaban (10 mg/kg) by oral gavage, while the rats in the control group were given rivaroxaban (10 mg/kg) only once. The plasma concentration of rivaroxaban in rats was then measured by UPLC‐MS/MS. In vitro data indicated that naringenin could decrease the metabolic clearance rate of rivaroxaban with the IC 50 value of 38.89 μM, and exhibited a mixed inhibition to rivaroxaban (Ki =54.91 μM, aKi =73.33 μM, a = 0.74). In vivo data in rats revealed that as compared with that of the control group, the AUC (0– t ) value of rats in the experimental group was increased from 2406.28 ± 519.69 μg/h/L to 4005.04 ± 1172.76 μg/h/L, the C max value was increased from 310.23 ± 85.76 μg/L to 508.71 ± 152.48 μg/L, and the V z / F and CL z / F were decreased from 23.03 ± 4.81 L/kg to 16.2 ± 8.42 L/kg, 4.26 ± 0.91 L/h/kg to 2.57 ± 0.73 L/h/kg, respectively. These data indicated that naringenin had an inhibitory effect on the pharmacokinetics of rivaroxaban in rats, suggesting that the DDIs between naringenin and rivaroxaban might occur when they were co‐administered in the clinic.

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“…For quantitation of plasma apixaban concentrations, samples were shipped by courier on dry ice to the Institute for Laboratory and Transfusion Medicine, Heart and Diabetes Center NRW, Bad Oeynhausen, Germany. Apixaban was quantitated as previously described ( 37 ) using automated online solid-phase extraction followed by LC/MS performed on protein-free samples and hence is species independent. In brief, proteins in the sample were initially precipitated by combining 100 μl of plasma sample with 200 μl of 0.1 M ZnSO 4 solution and 700 μl of isotope standard stock solution, mixing in a vortex device for 5 s followed by centrifugation (14,000 g, 5 min, RT).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and Biologic Activity of Apixaban in Healthy Dogs

et al. 2021

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Thrombosis is common in critically ill dogs and causes considerable morbidity and mortality. The direct factor Xa inhibitor apixaban is safe, efficacious, and convenient in humans. This study aimed to determine the pharmacokinetics (PK), bioactivity, protein binding, and bioavailability of apixaban following intravenous (IV) and oral (PO) administration to healthy dogs. Six healthy, adult, mixed-breed dogs were administered apixaban 0.18 mg/kg IV and then following a minimum 2-week washout period administered apixaban 0.2 mg/kg PO. Dogs were monitored using an apixaban-calibrated anti-Xa bioassay, prothrombin time (PT) and activated partial thromboplastin time (aPTT) and tissue-factor thromboelastography (TF-TEG). Plasma apixaban concentrations were measured using liquid chromatography-tandem mass spectrometry. Concentration-time plots were constructed, and PK modeling performed using compartmental methods. Administration of IV and PO apixaban was well-tolerated. Following IV administration, mean half-life was 4.1 h, and volume of distribution was 177 ml/kg. Apixaban was highly protein bound (98.6%). Apixaban concentrations and anti-Xa activity were highly correlated (R2 0.994, P < 0.0001). Intravenous apixaban significantly prolonged PT at time points up to 1 h, and aPTT at time points up to 0.25 h post-administration. Coagulation times were positively correlated with apixaban concentrations (PT R2 0.599, P < 0.0001; aPTT R2 0.430, P < 0.0001) and TF-TEG R-time was significantly prolonged 0.25 h post-administration. Following oral administration, mean bioavailability was 28.4%, lag time was 2 h, time to Cmax was 5 h and the apparent elimination half-life was 3.1 h. Oral apixaban significantly prolonged PT at 4, 6, and 8 h but aPTT and TF-TEG were not consistently affected by oral apixaban. Apixaban concentrations are best monitored using anti-Xa activity. Future studies should determine PK and bioactivity of other doses using commercial tablets and following multidose administration and establish safe, effective dosing ranges in sick dogs.

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Measurement of apixaban, dabigatran, edoxaban and rivaroxaban in human plasma using automated online solid-phase extraction combined with ultra-performance liquid chromatography-tandem mass spectrometry and its comparison with coagulation assays

Cited by 29 publications

References 38 publications

Point-of-care testing for emergency assessment of coagulation in patients treated with direct oral anticoagulants including edoxaban

Point-of-care testing for emergency assessment of coagulation in patients treated with direct oral anticoagulants including edoxaban

Naringenin has an inhibitory effect on rivaroxaban in rats both in vitro and in vivo

Pharmacokinetics and Biologic Activity of Apixaban in Healthy Dogs

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