Virginia Via Research Day Book 2026

Graduate Student Research Biomedical

05 EVALUATION OF SAFETY AND PHARMACOKINETICS OF A NOVEL NMDA RECEPTOR MODULATOR ON CANIS FAMILIARIS (DOGS).

Sudarshana Govindasamy; Blaise M. Costa, M.Pharm, PhD; Jennifer Davis, DVM, PhD, DACVIM, DACVCP; Joanne Tuohy, DVM, PhD, DACVS Corresponding author:sgovindasamy@vcom.edu 1&2 Pharmacology Division, VCOM-Virginia. 3 Department of Biomedical Sciences and Pathobiology 4 Department of Small Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia

Previous studies demonstrated central analgesic and stress-mitigating effects of a novel glutamate concentration -biased NMDA receptor modulator (CNS4) in mice. To translate the preclinical findings to a non-rodent species, the present study evaluated the safety and pharmacokinetics (PK) of CNS4 in a total of 24 adult Beagle dogs. A custom-made formulation was developed to dissolve CNS4 for subcutaneous (SC) injections. Initially, a dose escalation PK study (low: 5 mg/kg; medium: 10 mg/ kg; high: 50 mg/kg) was conducted, and PK data were analyzed using WinNonLin software. The time to reach maximum plasma concentration (Tmax) was 1.50 ± 0.87 (5 mg/kg), 1.67 ± 0.58 (10 mg/ kg), and 1.08 ± 0.88 hours (50 mg/kg). Furthermore, CNS4 exhibited a linear pharmacokinetic profile at 5 and 10 mg/kg doses, in contrast to the 50 mg/kg dose, which demonstrated nonlinear behavior across

multiple parameters. Notably, the apparent volume of distribution for the extravascular route (Vd/F) at 50 mg/ kg was 512 ± 229 L/kg, compared to 33.5 ± 12.5 L/ kg and 25.6 ± 3.67 L/kg for the 5 and 10 mg/kg doses, respectively. Subsequently, the feasibility of oral administration was evaluated using a single 50 mg/kg dose of CNS4 suspended in 0.5% sodium carboxymethyl cellulose and administered via oral gavage. PK analysis revealed that the Tmax via the oral route was approximately 1 hour, which is comparable to the SC route. An acute toxicity study conducted in four groups of dogs (vehicle, 5, 10, and 25 mg/kg) revealed no changes in behavior, food intake, or body weight following a single SC dose. Complete blood count, lipid profile, and electrolyte panels performed on plasma collected at days 0, 7, and 14 post-dosing showed no significant changes in biochemical parameters, except for potassium, which was elevated

in a dose-dependent manner on day 14 (4.39 ± 0.17, vehicle; 4.46 ± 0.10, 5 mg/kg; 4.74 ± 0.09, 10 mg/kg; 5.02 ± 0.11 mmol/L, 25 mg/kg). However, these values remained within the normal range (3.5 to 5.5 mmol/L). Together, the current study demonstrates the acceptable PK profile and safety of CNS4, as well as its versatility in route of administration. Analgesic efficacy studies of CNS4 in client-owned dogs, currently in progress, are expected to strengthen the dataset required for a U.S. FDA Investigational New Drug (IND) application and subsequent human trials of this mechanistically distinct novel NMDA receptor modulator.

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121 2026 Research Recognition Day