J. Yoon,1 J. Oh,1 Y. Kim,1 S. Cho,2 D. Lee,2 S. Shin,1 I. Jang,1 K. Yu,1 J. Chung3; 1Seoul National University Hospital, Jongno-gu, Seoul, Korea, Republic of, 2Vivozon, Inc., Sungbuk-gu, Seoul, Korea, Republic of, 3Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea, Republic of
BACKGROUND: VVZ-149, a dual antagonist on GlyT2 and 5HT2A, is an investigational analgesic product targeted for post-operative pain. This study explored the safety, tolerability and pharmacokinetics (PKs) of VVZ-149 after single and multiple intravenous administrations in healthy subjects.
METHODS: A randomized, double-blind, single ascending-dose (SAD) and multiple ascending-dose (MAD), placebo-controlled clinical trial was conducted in 67 healthy volunteers (NCT01905410). Subjects received 0.25-8 mg/kg of VVZ-149 in SAD study and 8-14 mg/kg/day for three days in MAD study. Serial blood and urine samples were collected for analysis of VVZ-149 and its active metabolite (VVZ-368). A non-compartmental analysis was used to calculate the PK parameters. Tolerability was evaluated based on vital signs, adverse events (AEs), clinical laboratory tests and electrocardiography.
RESULTS: In SAD study, the mean Cmax and AUClast of VVZ-149 and VVZ-368 increased with dose. The VVZ-149/VVZ-368 metabolic ratio ranged from 0.27 to 0.37. No dose-dependent changes were observed in Vd, CL or T1/2. The ranges of Tmax and T1/2 were 3-4.25 and 1.51-2.01 h for VVZ-149 and 4.5-8 and 3.96-6.86 h for VVZ-368, respectively. The fraction of VVZ-149 excreted unchanged in urine ranged from 0.03 to 0.05. In MAD study, the plasma exposure of VVZ-149 did not increase, but that of VVZ-368 increased with number of doses. The mean accumulation ratios of VVZ-149 and VVZ-368 were 0.97-1.31 and 1.46-2.49, respectively. No serious AEs occurred, and all AEs were transient and mild in intensity. No clinically significant changes were observed in safety variables.
CONCLUSION: The results suggest that 0.5-8 mg/kg of VVZ-149 can be safely administered for short period to patients with post-operative pain in Phase II clinical study.