Nonrodent safety and pharmacokinetics supporting clinical development of a novel N-methyl-D-aspartate receptor...

Previous studies demonstrated that CNS4, a glutamate concentration biased N-methyl-D-aspartate receptor modulator, produces central analgesic and stress mitigating effects in mice. To translate these findings to a nonrodent species, we evaluated the pharmacokinetics (PK) and safety of CNS4 in 21 adult beagle dogs. A custom formulation was developed for subcutaneous (SC) delivery, and an initial 2 dose PK study (5 and 10 mg/kg) was conducted. CNS4 achieved rapid absorption, with T_max values of 1.50 ± 0.87 hour (5 mg/kg) and 1.67 ± 0.58 hour (10 mg/kg). Pharmacokinetics were comparable across the limited doses studied, and apparent volumes of distribution for the extravascular route were 33.5 ± 12.5 and 25.6 ± 3.67 L/kg, respectively. To assess oral feasibility, a 50 mg/kg dose of CNS4 suspended in 0.5% carboxymethyl cellulose was first tested in mice and then in dogs. Oral administration in dogs resulted in rapid absorption, with a T_max of ∼1 hour, comparable to the SC route. Systemic tolerability was assessed in an acute toxicity study involving 4 groups (vehicle, 5, 10, and 25 mg/kg SC) of dogs. No changes in behavior, food intake, or body weight were observed over 14 days. Hematology, lipid panels, and electrolyte measurements collected on days 0 (predose), 7, and 14 revealed no significant CNS4 related abnormalities. Together, these findings demonstrate that CNS4 has an acceptable safety profile and predictable PK across SC and oral administration routes in dogs. This first-in-dog evaluation supports further development of CNS4 as a potential non opioid analgesic and stress mitigating therapeutic agent. SIGNIFICANCE STATEMENT: N-methyl-D-aspartate receptor subtypes are attractive therapeutic targets for chronic pain and post-traumatic stress disorder because of their critical role in emotional memory formation. This translational pharmacology study demonstrates the safety and predictable pharmacokinetics of a centrally acting analgesic and stress mitigating N-methyl-D-aspartate receptor modulator (CNS4) in dogs after single dose subcutaneous and oral administration.