Novel holistic pharmacokinetic model applied to plasma and urine concentrations of 2,5‐dihydroxybenzene sulphonate following administrations of calcium dobesilate and etamsylate to exercised horses

Paine, Stuart W.; Harding, Caitlin; Waller, Christopher C.; Zemenova, Jana; Viljanto, Marjaana; Habershon Butcher, Jocelyn; Hincks, Pamela R.

Abstract

AbstractCalcium dobesilate (CD) is a synthetic venoactive drug used in veterinary medicine to treat equine navicular disease. Etamsylate is a haemostatic agent used in horses for the treatment of exercise‐induced pulmonary haemorrhage. Both etamsylate and CD dissociate in the circulatory system with 2,5‐HBSA as the active drug. The aim of the research was to be able to provide detection time (DT) advice from pharmacokinetic (PK) studies in Thoroughbred horses to better inform trainers, and their veterinary surgeons, prescribing these substances for treatment of Thoroughbred racehorses. Two (pilot study) and six (final study) horses were given 28 and 9 repeated dose of CD (3 mg/kg BID) respectively. Two horses were each given a single intravenous (IV) dose of etamsylate (10 mg/kg). Plasma and urine 2,5‐HBSA concentrations were measured by liquid chromatography–tandem mass spectrometry (LC–MS/MS). The CD pilot study revealed that steady state could be reached with a few days and that 2,5‐HBSA in plasma and urine shows instability during storage at −20°C but appears stable at −80°C. A novel holistic non‐linear mixed‐effects three‐compartmental PK model was developed that described both plasma and urine concentrations of 2,5‐HBSA, from either CD or etamsylate administration. Typical values for 2,5‐HBSA clearance and bioavailability were 2.0 mL/min/kg and 28% respectively. Using the parameters obtained from this PK model, in conjunction with methodology developed by Toutain, afforded a possible screening limit (SL) that can regulate for a DT of 3 days in urine; however, a corresponding SL in plasma would be below current levels of detection. However, it is the responsibility of the individual racing authorities to apply their own risk management with regard to SLs and DTs.

Citation

Paine, S. W., Harding, C., Waller, C. C., Zemenova, J., Viljanto, M., Habershon Butcher, J., & Hincks, P. R. (2023). Novel holistic pharmacokinetic model applied to plasma and urine concentrations of 2,5‐dihydroxybenzene sulphonate following administrations of calcium dobesilate and etamsylate to exercised horses. Journal of Veterinary Pharmacology and Therapeutics, 46(6), 365-374. https://doi.org/10.1111/jvp.13387

• Journal Article Type: Article
• Acceptance Date: Apr 25, 2023
• Online Publication Date: May 31, 2023
• Publication Date: 2023-11
• Deposit Date: Jul 10, 2023
• Publicly Available Date: Jun 1, 2024
• Journal: Journal of Veterinary Pharmacology and Therapeutics
• Print ISSN: 0140-7783
• Electronic ISSN: 1365-2885
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 46
• Issue: 6
• Pages: 365-374
• DOI: https://doi.org/10.1111/jvp.13387
• Keywords: General Veterinary; Pharmacology
• Public URL: https://nottingham-repository.worktribe.com/output/21378469
• Publisher URL: https://onlinelibrary.wiley.com/doi/abs/10.1111/jvp.13387
• Additional Information: This is the peer reviewed version of the following article: Paine, S. W., Harding, C., Waller, C. C., Zemenova, J., Viljanto, M., Habershon Butcher, J., & Hincks, P. R. (2023). Novel holistic pharmacokinetic model applied to plasma and urine concentrations of 2,5-dihydroxybenzene sulphonate following administrations of calcium dobesilate and etamsylate to exercised horses. Journal of Veterinary Pharmacology and Therapeutics, which has been published in final form at https://doi.org/10.1111/jvp.13387 The article must be linked to Wiley’s version of record on Wiley Online Library