A Phase I Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Highly Selective NaV1.8 Inhibitor JKN2306 in Healthy Chinese Subjects.

JKN2306 is a novel, highly selective Nav1.8 inhibitor under development for the treatment of acute pain. This first-in-human study aimed to evaluate its safety, tolerability, pharmacokinetics, and food effect (FE). This was a single center, randomized, double-blind, placebo controlled, single ascending dose (SAD) and FEstudy in healthy Chinese subjects. In the SAD part, 44 subjects were randomized to receive a single oral dose of JKN2306 (10, 30, 100, 200, or 400 mg) or placebo. The FE part was a sequential, two-period crossover study in 14 subjects from the 200 mg SAD cohort, who received a single 200 mg dose under fasting and fed conditions. Forty-four subjects were enrolled and completed the study. JKN2306 was safe and well-tolerated across all doses. Treatment-emergent adverse events were mostly Grade 1, with no serious adverse events or dose limiting toxicities. No clinically significant effects on QTc interval were observed. JKN2306 was rapidly absorbed, with Tmax of 1.50-2.50 h. The t1/2 ranged from 13.93 to 29.82 h. Exposure (Cmax and AUC) increased approximately linearly with dose over the 10-400 mg range. Food intake delayed the median Tmax by 1 h and reduced Cmax by about 17%, but had no significant effect on AUC. JKN2306 exhibits a favorable safety and tolerability profile and predictable linear PK in healthy subjects. Food has a modest effect on the rate but not the extent of absorption. These findings support the further clinical development of JKN2306 for the treatment of acute pain. Trial Registration: chinadrugtrials.org.cn identifier: CTR20250247 and clinicaltrials.gov identifier: NCT07412938.