Pharmacokinetics and Biologic Activity of Apixaban in Healthy Dogs
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...
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| Format: | Article |
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Veterinary Science |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fvets.2021.702821/full |
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| author | Noelle D. Herrera Ingvild Birschmann Monika Wolny Mark G. Papich Marjory B. Brooks Robert Goggs |
| author_facet | Noelle D. Herrera Ingvild Birschmann Monika Wolny Mark G. Papich Marjory B. Brooks Robert Goggs |
| author_sort | Noelle D. Herrera |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T03:22:25Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2297-1769 |
| language | English |
| last_indexed | 2024-12-17T03:22:25Z |
| publishDate | 2021-07-01 |
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| series | Frontiers in Veterinary Science |
| spelling | doaj.art-8806e028a1314ed3867ce9f93cbeade22022-12-21T22:05:29ZengFrontiers Media S.A.Frontiers in Veterinary Science2297-17692021-07-01810.3389/fvets.2021.702821702821Pharmacokinetics and Biologic Activity of Apixaban in Healthy DogsNoelle D. Herrera0Ingvild Birschmann1Monika Wolny2Mark G. Papich3Marjory B. Brooks4Robert Goggs5Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, United StatesInstitute for Laboratory and Transfusion Medicine, Heart and Diabetes Center North Rhine-Westphalia, Bad Oeynhausen, GermanyInstitute for Laboratory and Transfusion Medicine, Heart and Diabetes Center North Rhine-Westphalia, Bad Oeynhausen, GermanyDepartment of Molecular Biomedical Sciences, North Carolina State College of Veterinary Medicine, Raleigh, NC, United StatesDepartment of Population Medicine and Diagnostic Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, United StatesDepartment of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, United StatesThrombosis 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.https://www.frontiersin.org/articles/10.3389/fvets.2021.702821/fullantithromboticanti-Xa activitydirect oral anticoagulantthrombosisthromboelastography |
| spellingShingle | Noelle D. Herrera Ingvild Birschmann Monika Wolny Mark G. Papich Marjory B. Brooks Robert Goggs Pharmacokinetics and Biologic Activity of Apixaban in Healthy Dogs Frontiers in Veterinary Science antithrombotic anti-Xa activity direct oral anticoagulant thrombosis thromboelastography |
| title | Pharmacokinetics and Biologic Activity of Apixaban in Healthy Dogs |
| title_full | Pharmacokinetics and Biologic Activity of Apixaban in Healthy Dogs |
| title_fullStr | Pharmacokinetics and Biologic Activity of Apixaban in Healthy Dogs |
| title_full_unstemmed | Pharmacokinetics and Biologic Activity of Apixaban in Healthy Dogs |
| title_short | Pharmacokinetics and Biologic Activity of Apixaban in Healthy Dogs |
| title_sort | pharmacokinetics and biologic activity of apixaban in healthy dogs |
| topic | antithrombotic anti-Xa activity direct oral anticoagulant thrombosis thromboelastography |
| url | https://www.frontiersin.org/articles/10.3389/fvets.2021.702821/full |
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