Pharmacokinetics and Pharmacodynamics of an Oral Formulation of Apixaban in Horses After Oral and Intravenous Administration
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 stud...
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Frontiers Media S.A.
2018-12-01
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| Series: | Frontiers in Veterinary Science |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fvets.2018.00304/full |
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| author | Priscila B. S. Serpa Marjory B. Brooks Thomas Divers Sally Ness Ingvild Birschmann Mark G. Papich Tracy Stokol |
| author_facet | Priscila B. S. Serpa Marjory B. Brooks Thomas Divers Sally Ness Ingvild Birschmann Mark G. Papich Tracy Stokol |
| author_sort | Priscila B. S. Serpa |
| collection | DOAJ |
| description | 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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| issn | 2297-1769 |
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| last_indexed | 2024-12-12T20:26:58Z |
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| spelling | doaj.art-c6549d7eabfc4326b166d86a0152b3782022-12-22T00:13:07ZengFrontiers Media S.A.Frontiers in Veterinary Science2297-17692018-12-01510.3389/fvets.2018.00304422721Pharmacokinetics and Pharmacodynamics of an Oral Formulation of Apixaban in Horses After Oral and Intravenous AdministrationPriscila B. S. Serpa0Marjory B. Brooks1Thomas Divers2Sally Ness3Ingvild Birschmann4Mark G. Papich5Tracy Stokol6Department of Population Medicine and Diagnostic Science, College of Veterinary Medicine, Cornell University, Ithaca, NY, United StatesDepartment of Population Medicine and Diagnostic Science, College of Veterinary Medicine, Cornell University, Ithaca, NY, United StatesDepartment of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United StatesDepartment of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United StatesInstitut für Laboratoriums-und Transfusionsmedizin, Herz-und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Bad Oeynhausen, GermanyDepartment of Molecular Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United StatesDepartment of Population Medicine and Diagnostic Science, College of Veterinary Medicine, Cornell University, Ithaca, NY, United StatesHorses 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.https://www.frontiersin.org/article/10.3389/fvets.2018.00304/fullfactor Xadirect oral anticoagulantEHV-1platelet activationequine |
| spellingShingle | Priscila B. S. Serpa Marjory B. Brooks Thomas Divers Sally Ness Ingvild Birschmann Mark G. Papich Tracy Stokol Pharmacokinetics and Pharmacodynamics of an Oral Formulation of Apixaban in Horses After Oral and Intravenous Administration Frontiers in Veterinary Science factor Xa direct oral anticoagulant EHV-1 platelet activation equine |
| title | Pharmacokinetics and Pharmacodynamics of an Oral Formulation of Apixaban in Horses After Oral and Intravenous Administration |
| title_full | Pharmacokinetics and Pharmacodynamics of an Oral Formulation of Apixaban in Horses After Oral and Intravenous Administration |
| title_fullStr | Pharmacokinetics and Pharmacodynamics of an Oral Formulation of Apixaban in Horses After Oral and Intravenous Administration |
| title_full_unstemmed | Pharmacokinetics and Pharmacodynamics of an Oral Formulation of Apixaban in Horses After Oral and Intravenous Administration |
| title_short | Pharmacokinetics and Pharmacodynamics of an Oral Formulation of Apixaban in Horses After Oral and Intravenous Administration |
| title_sort | pharmacokinetics and pharmacodynamics of an oral formulation of apixaban in horses after oral and intravenous administration |
| topic | factor Xa direct oral anticoagulant EHV-1 platelet activation equine |
| url | https://www.frontiersin.org/article/10.3389/fvets.2018.00304/full |
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