Safety, tolerability, pharmacokinetics, and pharmacodynamics of a novel kappa opioid receptor agonist ZYKR1: a randomized double-blind placebo-control phase 1 study in healthy adult human participants.
Naunyn Schmiedebergs Arch Pharmacol
; 397(7): 4737-4745, 2024 07.
Article
de En
| MEDLINE
| ID: mdl-38141084
ABSTRACT
To perform first-in-human single-dose escalation trial of ZYKR1, which is a potent, selective, and peripherally-restricted kappa opioid receptor agonist, is the purpose of this study. This randomized, double-blind, placebo-controlled single ascending dose study conducted at Zydus Research Centre, Ahmedabad, India included healthy male participants aged 18-55 years and weighing > 50 kg. The primary objective was to evaluate the safety and tolerability of ZYKR1. The secondary objective was to evaluate the pharmacokinetics and pharmacodynamics (PD) of ZYKR1. Participants received ZYKR1 (0.5 - 6 mcg/kg) or placebo infused intravenously in 15 ± 1 min. Of total five dose groups (0.5 - 6 mcg/kg), each group included eight participants with six and two randomized to ZYKR1 and placebo, respectively. Three participants experienced six treatment-emergent adverse events (TEAEs); two were gastrointestinal disorders (nausea and vomiting at 2 mcg/kg); and four were related to the nervous system (headache (at 2 mcg/kg) and facial tingling, facial numbness and paresthesia (at 6 mcg/kg)); all TEAEs were mild and resolved without sequelae. The Cmax of ZYKR1 was achieved after 15 - 20 min of start of infusion. The mean exposures (Cmax and AUC0 - t) increased in a dose-proportional manner. The mean t1/2 ranged from 2.20 to 2.98 h across the dose range. Increase in the mean prolactin level was significantly higher in treatment groups compared with that in the placebo group. Intravenous ZYKR1 at doses up to 6 mcg/kg showed acceptable safety and tolerability and demonstrated a short half-life with principal route of excretion as renal. ZYKR1 displayed a potent PD effect reflected by increased prolactin levels, supporting further study in patients. Trial registration Clinical Trial Registry of India CTRI/2018/07/014927. Date of registration 18/07/2018.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Récepteur kappa
Limites:
Adolescent
/
Adult
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Humans
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Male
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Middle aged
Langue:
En
Journal:
Naunyn Schmiedebergs Arch Pharmacol
/
Naunyn-Schmiedeberg's arch. pharmacol. (Internet)
/
Naunyn-Schmiedeberg's archives of pharmacology (Internet)
Année:
2024
Type de document:
Article
Pays d'affiliation:
Inde
Pays de publication:
Allemagne