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Pharmacokinetics of grapiprant and effects on TNF-alpha concentrations following oral administration to horses.
Abstract: Grapiprant is a prostaglandin E2 receptor antagonist that has been found to be an effective anti-inflammatory in dogs and that is devoid of some of the adverse effects associated with traditional NSAIDs that elicit their effects through inhibition of PGE2 production. Previously published reports have described the pharmacokinetics of this drug in horses when administered at 2 mg/kg; however, pharmacodynamic effects in this species have yet to be described. The objective of the current study was to describe the pharmacokinetics and pharmacodynamics of grapiprant at a higher dose. Eight horses received a single oral administration of 15 mg/kg. Plasma concentrations were determined for 96 h using liquid chromatography-tandem mass spectrometry. Non-compartmental analysis was used to determine pharmacokinetic parameters. Pharmacodynamic effects were assessed ex vivo by stimulating blood samples with PGE2 and determining TNF-ɑ concentrations. Maximum concentration, time to maximum concentration and area under the curve were 327.5 (188.4-663.0) ng/ml, 1 (0.75-2.0) hour and 831.8 (512.6-1421.6) h*ng/ml, respectively. The terminal half-life was 11.1 (8.27-21.2) hr. Significant stimulation of TNF alpha was noted for 2-4 h post-drug administration. Results of this study suggest a short duration of EP4 receptor engagement when administered at a dose of 15 mg/kg.
© 2022 John Wiley & Sons Ltd.
Publication Date: 2022-06-01 PubMed ID: 35652132PubMed Central: PMC10919302DOI: 10.1111/jvp.13076Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
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The research article summarizes a study investigating the behavior and effects of a drug called grapiprant, a potent anti-inflammatory, in horses. The study particularly focused on the drug’s pharmacokinetics (how the drug moves within the body) and pharmacodynamics (the drug’s effects on the body) when given at a higher dosage than previously studied.
Objective of the Study
- The goal of this study was to explore the pharmacokinetics and pharmacodynamics of grapiprant, specifically when administered in horses at a higher dose than previously reviewed.
- Grapiprant is a receptor antagonist that opposes the activity of a prostaglandin E receptor. This receptor plays a key role in inflammation, so inhibiting it can reduce inflammatory responses.
- It’s notable that grapiprant lacks some of the adverse effects seen in traditional nonsteroidal anti-inflammatory drugs (NSAIDs) which work by inhibiting prostaglandin E (PGE) production.
Methodology
- Eight horses were given a single oral dose of 15 mg/kg of grapiprant.
- Over a 96-hour period, plasma concentrations were measured using liquid chromatography-tandem mass spectrometry, a technique for identifying and quantifying substances in a sample.
- Pharmacokinetic parameters such as maximum concentration, time to maximum concentration, and area under the curve were determined through non-compartmental analysis.
- The effects of the drug were assessed ex vivo (outside the body) by stimulating blood samples with PGE and measuring the subsequent concentrations of TNF-alpha (a protein involved in systemic inflammation).
Findings
- Key pharmacokinetic values included a maximum concentration of 327.5 ng/ml, time to maximum concentration of 1 hour and an area under the curve measurement of 831.8 h*ng/ml. The terminal half-life was also found to be 11.1 hours.
- A significant stimulation of TNF alpha was observed for 2-4 hours after the drug was given.
- These results suggest that grapiprant engagement with the prostaglandin E receptor (EP4) lasts only a short duration when given at a dose of 15 mg/kg.
Cite This Article
APA
Hoffmann SL, Seminoff K, McKemie DS, Kass PH, Knych HK.
(2022).
Pharmacokinetics of grapiprant and effects on TNF-alpha concentrations following oral administration to horses.
J Vet Pharmacol Ther, 45(5), 467-472.
https://doi.org/10.1111/jvp.13076 Publication
Researcher Affiliations
- K.L Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California, Davis, California, USA.
- K.L Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California, Davis, California, USA.
- K.L Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California, Davis, California, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, California, USA.
- K.L Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California, Davis, California, USA.
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California, USA.
MeSH Terms
- Administration, Oral
- Animals
- Area Under Curve
- Half-Life
- Horses / blood
- Imidazoles
- Prostaglandins E
- Pyridines
- Sulfonylurea Compounds / pharmacokinetics
- Tumor Necrosis Factor-alpha
Grant Funding
- T35 OD010956 / NIH HHS
Conflict of Interest Statement
CONFLICTS OF INTEREST. None of the authors have any conflicts of interest to report.
References
This article includes 16 references
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Citations
This article has been cited 2 times.- Cassemiche A, Schoffit S, Manassero M, Kohlhauer M. Comparison of grapiprant and meloxicam for management of postoperative joint pain in dogs: A randomized, double-blinded, prospective clinical trial. J Vet Intern Med 2024 Jul-Aug;38(4):2324-2332.
- Mercer MA, Davis JL, McKenzie HC. The Clinical Pharmacology and Therapeutic Evaluation of Non-Steroidal Anti-Inflammatory Drugs in Adult Horses. Animals (Basel) 2023 May 10;13(10).
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