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J Clin Pharmacol. 2018 Jan;58(1):64-73. doi: 10.1002/jcph.973. Epub 2017 Aug 16.

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

Author information

1
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
2
Clinical Trial Center, Ajou University Medical Center, Suwon, Republic of Korea.
3
Center for Clinical Pharmacology, Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea.
4
Vivozon, Inc., Seoul, Republic of Korea.
5
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Republic of Korea.

Abstract

VVZ-149, a dual antagonist of GlyT2 and 5HT2 A 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.

KEYWORDS:

analgesic; first-in-human study; pharmacokinetics; phase 1; safety

PMID:
28815639
DOI:
10.1002/jcph.973
[Indexed for MEDLINE]

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