Safety, Tolerability, and Pharmacokinetic Characteristics ofￂ a Novel Nonopioid Analgesic, VVZ-149 Injections in Healthy Volunteers: A First-in-Class, First-in-Human Study

• Published in: Journal of clinical pharmacology 2018-01, Vol.58 (1), p.64
• Main Authors: Oh, Jaeseong, Lee, SeungHwan, Kim, Anhye, Yoon, Jangsoo, Jang, Kyungho, Lee, Doo H, Cho, Sunyoung, Lee, Sang Rim, Yu, Kyung-Sang, Chung, Jae-Yong
• Format: Article
• Language: English
• Subjects: Analgesics; Animal models; Clinical trials; Computer simulation; Drug therapy; Glycine transporter; Inflammation; Intravenous administration; Intravenous infusion; Neuralgia; Pharmacokinetics; Urine
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1002/jcph.973

VVZ-149, a dual antagonist of GlyT2 and 5HT2A receptors, is an investigational analgesic with a novel mechanism of action that is currently under early-stage clinical development as an injectable agent for the treatment of postoperative pain. Here, the safety, tolerability, and pharmacokinetics of VVZ-149 injections in healthy male volunteers were explored in a randomized, double-blind, single- and multiple-ascending-dose (SAD and MAD, respectively), placebo-controlled clinical study. Subjects randomly received a 4-hour intravenous infusion of 0.25-8 mg/kg VVZ-149 or placebo in the SAD study (n = 46) or a 4-hour intravenous infusion of 4-7 mg/kg VVZ-149 or placebo twice daily for 3 days in the MAD study (n = 20). Serial blood and urine samples were collected for the pharmacokinetic analysis of VVZ-149 and its active metabolite (VVZ-368). Noncompartmental and compartmental pharmacokinetic analyses were performed. Various dosing scenarios were simulated to identify the adequate dosing regimen for the subsequent trials. Plasma exposure to VVZ-149 and VVZ-368 showed a dose-proportional increase. VVZ-149 did not accumulate in the plasma, whereas the plasma concentration of VVZ-368 increased by 1.23- to 2.49-fold after the fifth and sixth doses, respectively, in the MAD trial. Among the simulated dosing regimens, a loading dose followed by a maintenance dose was found to be an optimal dosing regimen, yielding the effective concentration estimated from animal studies in rat models of neuropathic or inflammatory pain. Single- or multiple-dose administration of VVZ-149 was generally well tolerated. These results showed that 0.5-8 mg/kg VVZ-149 exhibited linear pharmacokinetic characteristics and can be safely administered in further clinical studies.