Evaluation of Safety, Pharmacokinetic, and Pharmacodynamic Characteristics of a Novel Dual mGluR5/5-HT2AR Antagonist (VVZ-2471) in a Randomized, Double-Blind, First-in-Human Study.

backgroundVVZ-2471 is a dual-target compound that simultaneously inhibits both metabotropic glutamate receptor subtype 5 and serotonin receptor subtype 2A. Preclinical studies have supported VVZ-2471 as a promising candidate for opioid use disorder. This study aimed to evaluate the safety and pharmacokinetic (PK)-pharmacodynamic (PD) characteristics of VVZ-2471 capsules in healthy Korean adults.

methodsA phase I, double blind, placebo controlled, single ascending dose (SAD) and multiple ascending dose (MAD) study was conducted in healthy adult males. In the SAD study, participants received a single oral dose of VVZ-2471 ranging from 25 to 600 mg, including a satellite food-effect group receiving 200 mg. In the MAD study, participants received 200 mg once daily (QD), 200 mg twice daily, and 400 mg QD for 7 days. Plasma and urine samples were collected for the PK analyses. Safety analysis was based on adverse events, clinical laboratory tests, vital signs, physical examinations, 12-lead electrograms, oxygen saturation monitoring, and the Beck Depression Inventory-II test. The potential of VVZ-2471 for treating addiction was explored using a well-established questionnaire on smoking urges (QSU-Brief) consisting of ten items.

resultsA total of 49 and 24 healthy Korean adult males completed the SAD and MAD study, respectively. The overall demographic characteristics of participants who received VVZ-2471 or placebo in the SAD and MAD studies were generally comparable. Following a single oral dose of VVZ-2471 up to 600 mg, the area under the concentration-time curve (AUC) increased proportionally with the dose. After repeated administration, the accumulation ratio of VVZ-2471 ranged from 1.4 to 2.0. In the fed state, the maximum plasma concentration and AUC of VVZ-2471 decreased to 0.78-fold and 0.61-fold, respectively, compared with the fasting state. Urinary excretion was marginal. The most common adverse events were nausea and dizziness. Among 29 smokers, participants given VVZ-2471 at 200 mg or higher had reduced smoking urges compared with the placebo.

conclusionsVVZ-2471 was well tolerated up to a single oral dose of 600 mg and a daily oral dose of 400 mg for 7 days. While preliminary, a trend of reducing smoking urges was observed in the VVZ-2471 group. REGISTRATION: Clinical Research Information Service (CRiS), Republic of Korea (a primary registry in the World Health Organization (WHO) Registry Network) identifier no. KCT000889.