Journal Article

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

Kansagra, Kevinkumar A., Momin, Taufik, Ghoghari, Ashok, Patel, Harilal V., Shah, Chintan, Parmar, Deven V., Patel, Hardik B., Parmar, Gordhan

2024

Overview

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 C max of ZYKR1 was achieved after 15 − 20 min of start of infusion. The mean exposures ( C max and AUC 0 − t ) increased in a dose-proportional manner. The mean t 1/2 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.

• Publisher: Springer Berlin Heidelberg,Springer Nature B.V
• Subject: Adolescent / Adult / Agonists / Azabicyclo Compounds / Biomedical and Life Sciences / Biomedicine / Clinical trials / Complications / Dose-Response Relationship, Drug / Double-Blind Method / Gastrointestinal diseases / Healthy Volunteers / Humans / Male / Middle Aged / Narcotics / Nervous system / Neurosciences / Oligopeptides / Opioid receptors (type kappa) / Paresthesia / Pharmacodynamics / Pharmacokinetics / Pharmacology/Toxicology / Placebos / Prolactin / Receptors, Opioid, kappa - agonists / Renal function / Safety / Young Adult