Rational quinidine dosage regimen for atrial fibrillation in Thoroughbred racehorses based on population pharmacokinetics.
Abstract: Quinidine (QND) sulfate is an effective treatment for atrial fibrillation (AF) in horses, and several dosage regimens have been proposed to address its wide variability in response and potential adverse effects. The purpose of this study was to analyze the variability in plasma quinidine concentrations using population pharmacokinetics to determine an effective and safe dosage regimen for Thoroughbred horses. Unassigned: Six healthy Thoroughbred horses were treated with 20 mg/kg quinidine sulfate dihydrate (16.58 mg/kg QND base) administered PO or 5 mg/kg quinidine hydrochloride monohydrate (4.28 mg/kg QND base) administered IV (single administration), and blood samples were taken regularly. Four healthy horses were treated with 20 mg/kg quinidine sulfate dihydrate administered twice (every 6 h) via PO route. For the other 19 Thoroughbred racehorses that developed AF, blood samples were taken during quinidine therapy. Quinidine concentrations were measured in all plasma samples using liquid chromatography with tandem mass spectrometry, and the data from 29 horses were modeled using a nonlinear mixed-effects model, followed by Monte Carlo simulations (MCS). Unassigned: The median quinidine concentration for successful sinus rhythm conversion was 2.0 μg/mL (range: 0.5-2.7 μg/mL) in AF horses, while a median concentration of 3.8 μg/mL (range: 1.6-5.1 μg/mL) showed adverse effects. MCS predicted that plasma quinidine concentrations for quinidine sulfate dihydrate PO administration (loading dose: 30 mg/kg, maintenance dose: 6.5 mg/kg q 2 h) reached 1.4, 2.0 and 2.7 μg/mL in 90, 50 and 10% of the horse populations, respectively. Increasing the loading dose to 45 mg/kg and the maintenance dose to 9 mg/kg q 2 h, the plasma concentrations achieved were 1.9, 2.8, and 3.8 μg/mL in 90, 50, and 10% of horse populations, respectively. Unassigned: Using simulations, different empirical dosing regimens were proposed to achieve plasma quinidine concentrations immediately or progressively, representing a tradeoff between optimizing therapeutic effects and minimizing adverse effects. A combination of these dosing regimens is recommended to gradually increase the therapeutic concentration levels of quinidine for safe and effective treatment of AF in racehorses.
Copyright © 2024 Kuroda, Minamijima, Kinman, Takahashi, Ebisuda, Inoue, Ishikawa, Mita, Tamura, Nukada, Toutain and Ohta.
Publication Date: 2024-10-07 PubMed ID: 39439824PubMed Central: PMC11493839DOI: 10.3389/fvets.2024.1454342Google Scholar: Lookup
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- Journal Article
Summary
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This research presents an optimized dosing regimen for using quinidine to treat irregular heartbeats in Thoroughbred racehorses, based on pharmacokinetic analysis.
Study and Method
- The study aims to determine a safe and effective dosage plan for using quinidine sulfate (QND), a popular medication for Atrial Fibrillation (AF) or abnormal heart rhythm, in Thoroughbred horses. Despite its effectiveness, there are downsides to QND, such as its inconsistent response and possible side effects, which led the researchers to explore new dosage methods.
- Six healthy Thoroughbred horses were given QND orally, or intravenously as a one-time dosage and had their blood tested regularly. Another four healthy horses received two oral doses of the same treatment six hours apart.
- To study results in AF-affected horses, 19 Thoroughbred racehorses with AF had their blood sampled during their QND treatment. All blood samples were analyzed using liquid chromatography with tandem mass spectrometry, a testing method well-suited for detecting drug concentration levels in blood.
- This data, collected from a total of 29 horses, was modelled with a non-linear mixed-effects approach, followed by Monte Carlo simulations, a mathematical technique that predicts the potential outcomes of an unknown variable.
Results
- The study found that in AF horses, a median QND concentration of 2.0 μg/mL successfully converted their heart rhythm to normal. However, a higher median concentration of 3.8 μg/mL led to unwanted side effects.
- According to the simulations, specific QND dosing regimen achieved the required QND concentration for 90%, 50%, and 10% of the horse population immediately or gradually. This balance between minimizing side effects and optimizing treatment effect is critical in the proposed dosage methods.
Conclusion
- Considering the simulation results, researchers proposed various dosing schedules that would either immediately or gradually achieve the desired plasma quinidine concentration.
- The proposed regimens are designed to carefully increase the concentration of quinidine to reach therapeutic levels, thus balancing the potential risk of side effects alongside the treatment’s effectiveness. Such a combination of treatment schedules is found to be both safe and effective for managing AF in racehorses.
Cite This Article
APA
Kuroda T, Minamijima Y, Kinman CK, Takahashi Y, Ebisuda Y, Inoue K, Ishikawa H, Mita H, Tamura N, Nukada T, Toutain PL, Ohta M.
(2024).
Rational quinidine dosage regimen for atrial fibrillation in Thoroughbred racehorses based on population pharmacokinetics.
Front Vet Sci, 11, 1454342.
https://doi.org/10.3389/fvets.2024.1454342 Publication
Researcher Affiliations
- Clinical Veterinary Medicine Division, Equine Research Institute, Japan Racing Association, Shimotsuke, Japan.
- Drug Analysis Department, Laboratory of Racing Chemistry, Utsunomiya, Japan.
- Drug Analysis Department, Laboratory of Racing Chemistry, Utsunomiya, Japan.
- Sports Science Division, Equine Research Institute, Japan Racing Association, Shimotsuke, Japan.
- Sports Science Division, Equine Research Institute, Japan Racing Association, Shimotsuke, Japan.
- Ritto-Training Center Racehorse Hospital, Japan Racing Association, Ritto, Japan.
- Ritto-Training Center Racehorse Hospital, Japan Racing Association, Ritto, Japan.
- Clinical Veterinary Medicine Division, Equine Research Institute, Japan Racing Association, Shimotsuke, Japan.
- Clinical Veterinary Medicine Division, Equine Research Institute, Japan Racing Association, Shimotsuke, Japan.
- Ritto-Training Center Racehorse Hospital, Japan Racing Association, Ritto, Japan.
- Comparative Biomedical Sciences, The Royal Veterinary College, London, United Kingdom.
- INTHERES, Université de Toulouse, INRAE, ENVT, Toulouse, France.
- Clinical Veterinary Medicine Division, Equine Research Institute, Japan Racing Association, Shimotsuke, Japan.
Conflict of Interest Statement
TK, YM, CK, YT, YE, KI, HI, HM, NT, TN, and MO were employed by Japan Racing Association. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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