Taisuke Kuroda ^1* Yohei Minamijima ² Christopher K. Kinman ² Yuji Takahashi ¹ Yusaku Ebisuda ¹ Kaori Inoue ³ Hiroshi Ishikawa ³ Hiroshi Mita ¹ Norihisa Tamura ¹ Toshio Nukada ³ Pierre-Louis TOUTAIN ^4,5 Minoru Ohta ¹

• ¹ Equine Research Institute, Japan Racing Association, Shimotsuke, Japan
• ² Laboratory of Racing Chemistry, Utsunomiya, Tochigi, Japan
• ³ Ritto training center, Japan Racing Association, Ritto, Japan
• ⁴ Department of Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, England, United Kingdom
• ⁵ Ecole Nationale Vétérinaire de Toulouse (ENVT), Toulouse, Occitanie, France

Introduction: 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. Methods: 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 modelled using a nonlinear mixed-effects model, followed by Monte Carlo simulations (MCS). Results: 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. Discussion: 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.