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.

Abstract

Background: VVZ-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.

Methods: A 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.

Results: A 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.

Conclusions: VVZ-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.