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

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

doi:10.1007/s00210-023-02912-9

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. 2023 Dec 23. doi: 10.1007/s00210-023-02912-9. Online ahead of print.

Authors

Kevinkumar A Kansagra¹, Taufik Momin², Hardik B Patel³, Chintan Shah³, Gordhan Parmar³, Ashok Ghoghari³, Harilal V Patel³, Deven V Parmar²

Affiliations

¹ Zydus Research Centre, Clinical R & D, Zydus Lifesciences Limited, Sarkhej-Bavla N. H. No. 8 A, Moraiya, Ahmedabad, 382213, Gujarat, India. kevinkumarkansagra@zyduslife.com.
² Zydus Therapeutics Inc., Pennington, NJ, USA.
³ Zydus Research Centre, Clinical R & D, Zydus Lifesciences Limited, Sarkhej-Bavla N. H. No. 8 A, Moraiya, Ahmedabad, 382213, Gujarat, India.

PMID: 38141084
DOI: 10.1007/s00210-023-02912-9

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 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.

Keywords: Kappa opioid agonist; Opioid; Pharmacodynamics; Pharmacokinetic; Safety; ZYKR1.