Evaluation of an oral direct factor Xa inhibitor anticoagulant in healthy adult horses

Rodríguez-Pozo, Maria L.; Armengou, Lara; Monreal, Luís; Viu, Judit; Cesarini, Carla; Jose‐Cunilleras, Eduard

doi:10.1111/vec.12540

Cited by 3 publications

(4 citation statements)

References 32 publications

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“…In terms of peak time, peak plasma activity of rivaroxaban was reached 2‐4 hours after administration in humans . We selected 3 hours post‐administration as the peak time point according to previous studies in humans . A recent study reported a peak time point of 1.5‐2 hours after dosing in dogs .…”

Section: Discussionmentioning

confidence: 99%

“…29 We selected 3 hours post-administration as the peak time point according to previous studies in humans. 10,22 A recent study reported a peak time point of 1.5-2 hours after dosing in dogs. 14 However, the dogs in our study were not allowed to fast during the study period; thus, the peak time may have been slightly delayed because food can interfere with the absorption of rivaroxaban, leading to delayed peak times of 0.5-1.5 hours compared to those in the fasted state.…”

Section: Discussionmentioning

confidence: 99%

“…Spearman correlation coefficients were calculated to compare plasma anti‐Xa concentration with other coagulation variables and doses. Peak time was regarded at 3 hours after drug administration based on previous reports . Spearman correlation coefficients were calculated between ratios (peak time PT, R value of TEG/baseline PT, R value of TEG) and anti‐Xa concentration.…”

Section: Methodsmentioning

confidence: 99%

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Therapeutic monitoring of rivaroxaban in dogs using thromboelastography and prothrombin time

Bae

Kim

et al. 2019

Veterinary Internal Medicne

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Background The chromogenic anti‐Xa assay, the gold standard for monitoring the anti‐Xa effect of rivaroxaban, is not available as a cage‐side diagnostic test for use in a clinical setting. Hypothesis/Objectives To evaluate clinical modalities for measuring the anticoagulant effects of rivaroxaban using a point‐of‐care prothrombin time (PT) and thromboelastography (TEG). Animals Six healthy Beagle dogs. Methods Prospective, experimental study. Four different doses of rivaroxaban (0.5, 1, 2, and 4 mg/kg) were administered PO to dogs. Single PO and 3 consecutive dosing regimens also were assessed. Plasma rivaroxaban concentration was determined using a chromogenic anti‐Xa assay, point‐of‐care PT, and TEG analysis with 4 activators (RapidTEG, 1 : 100 tissue factor [TF100], 1 : 3700 tissue factor [TF3700], and kaolin), and results were compared. Spearman correlation coefficients were calculated between ratios (peak to baseline PT; peak reaction time [R] of TEG to baseline [R] of TEG) and anti‐Xa concentration. Results Anti‐Xa concentration had a significant correlation with point‐of‐care PT (R = 0.82, P < .001) and RapidTEG‐TEG, TF100‐TEG, and TF3700‐TEG (R = 0.76, P < .001; R = 0.82, P < .001; and R = 0.83, P < .001, respectively). Conclusions and Clinical Importance Overall, a 1.5‐1.9 × delay in PT and R values of TEG 3 hours after rivaroxaban administration is required to achieve therapeutic anti‐Xa concentrations of rivaroxaban in canine plasma. The R values of TEG, specifically using tissue factors (RapidTEG, TF100, TF3700) and point‐of‐care PT for rivaroxaban can be used practically for therapeutic monitoring of rivaroxaban in dogs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Therapeutic monitoring of rivaroxaban in dogs using thromboelastography and prothrombin time

Bae

Kim

et al. 2019

Veterinary Internal Medicne

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“…An unidentified direct oral anti-Xa inhibitor was administered to nine horses at a dose of 0.125 mg/kg PO at 24 h intervals for 4 days, however prophylactic anti-Xa activity was detected in only one animal after the first dose (32). To our knowledge, apixaban has not yet been tested in horses.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of an Oral Formulation of Apixaban in Horses After Oral and Intravenous Administration

et al. 2018

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Horses with inflammatory and infectious disorders are often treated with injectable heparin anticoagulants to prevent thrombotic complications. In humans, a new class of direct oral acting anticoagulants (DOAC) appear as effective as heparin, while eliminating the need for daily injections. Our study in horses evaluated apixaban, a newly approved DOAC for human thromboprophylaxis targeting activated factor X (Xa). Our goals were to: (1) Determine pharmacokinetics and pharmacodynamics of apixaban after oral (PO) and intravenous (IV) administration in horses; (2) Detect any inhibitory effects of apixaban on ex vivo Equid herpesvirus type 1 (EHV-1)-induced platelet activation, and (3) Compare an anti-Xa bioactivity assay with ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) for measuring apixaban concentrations. In a blinded placebo-controlled cross-over study, five horses received a single dose (0.2 mg/kg) of apixaban or placebo PO or IV. Blood was collected before and at 3 (IV) or 15 (PO) min, 30 and 45 min, and 1, 2, 3, 4, 6, 8, and 24 h after dosing for measuring apixaban UPLC-MS concentrations and anti-Xa activity. Pharmacodynamic response was measured in a dilute prothrombin time (dPT) assay. Flow cytometric EHV-1-induced platelet P-selectin expression and clinical pathologic safety testing were performed at baseline, 2 and 24 h and baseline and 24 h, respectively. We found no detectable apixaban in plasma PO administration. After IV administration, plasma apixaban levels followed a two-compartment model, with concentrations peaking at 3 min and decreasing to undetectable levels by 8 h. The elimination half-life was 1.3 ± 0.2 h, with high protein binding (92–99%). The dPT showed no relationship to apixaban UPLC-MS concentration and apixaban did not inhibit EHV-1-induced platelet activation after IV dosing. Apixaban anti-Xa activity showed excellent correlation to UPLC-MS (r2 = 0.9997). Our results demonstrate that apixaban has no apparent clinical utility as an anticoagulant for horses due to poor oral availability.

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Hemostasis, Surgical Bleeding, and Transfusion

Mudge¹

2019

Equine Surgery

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Evaluation of an oral direct factor Xa inhibitor anticoagulant in healthy adult horses

Abstract: At the low end of the recommended dose in people this oral formulation of DiXaI did not reach prophylactic plasma antifactor Xa activity in this group of healthy adult horses. Further studies are warranted in order to establish the prophylactic dose for horses.

Cited by 3 publications

References 32 publications

Therapeutic monitoring of rivaroxaban in dogs using thromboelastography and prothrombin time

Therapeutic monitoring of rivaroxaban in dogs using thromboelastography and prothrombin time

Pharmacokinetics and Pharmacodynamics of an Oral Formulation of Apixaban in Horses After Oral and Intravenous Administration

Hemostasis, Surgical Bleeding, and Transfusion

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