Safety and Tolerability of ENA-001 for the Management of Pharmacologically-induced Respiratory Depression

Safety and Tolerability of ENA-001 for the Management of Pharmacologically-induced Respiratory Depression

Background: Some of the most common pharmacologic agents for anesthesia and pain management induce depression of the respiratory drive (Respiratory depression; RD).¹ This RD is a potent contributor to pulmonary complications following anesthesia¹, a substantial risk to use of drugs for pain management² and the leading cause of death amongst drug abusers³. ENA-001 is a novel respiratory stimulant whose mechanism of action is independent of the underlying cause of RD (i.e., acts on BK_Ca channels at the carotid bodies).  

Purpose/Objectives:

The aim of this study was to examine the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics for continuous intravenous (IV) infusion of ENA-001 in healthy adults.

Method:

Eighteen adult volunteers participated in a blinded, placebo-controlled, 4-period ascending, repeated single-dose study comparing the effects of ENA-001 administered via IV at rates of 0.96, 1.44, 1.92 mg/kg/h over a 2-hour duration to placebo.

Results: Seventeen of the 18 participants completed the study.  One subject prior to the second dose discontinued the study by withdrawing consent due to personal reasons. The subject received placebo treatment and completed the dosing session with one AE reported as a mild headache with onset during the treatment period.  Three participants (17%) did not report any adverse events. Fourteen participants (78%) reported at least one drug-related adverse event during the study. The most common adverse events were nausea (50%), infusion related reactions (44%), headache (22%), dizziness (17%), vomiting (11%), abdominal pain (17%), hyperventilation (11%), and diarrhea (11%).  All AEs were mild to moderate in severity and resolved spontaneously.  There were no significant changes in blood pressure during the infusion compared to placebo.  Minute ventilation was significantly increased while end tidal CO₂ (ETCO₂) was significantly decreased compared to placebo. Hemoglobin O₂ saturation (SpO₂) increased after initiation of infusion of the high dose. C_max was reached at the end of the infusion (2 hrs) with a distribution half-life of less than 30 minutes and a terminal half-life of 5.2-8.1 hrs.

Conclusions: ENA-001 was generally safe and well tolerated over the dose range administered. ENA-001 was able to drive hyperventilation in healthy subjects with a dose dependency. Peak plasma concentrations and mean systemic exposure were dose-proportional in the dose range studied. The PK fits a two-compartmental model with distribution half-life, terminal half-life, steady-state volume and plasma clearance largely dose-independent. Further study is required to determine the effects of ENA-001 on prevention and treatment of pharmacologically-induced RD.

References: 1. M Karcz, PJ Papadakos. Respiratory complications in the postanesthesia care unit: A review of pathophysiological mechanisms. Can J Respir Ther 2013;49(4):21-29.
2. Weingarten TN, Warner LL, Sprung J. Timing of postoperative respiratory emergencies: when do they really occur? Curr Opin Anaesthesiol. 2017;30(1):156-162.
3. Fox LM, Hoffman RS, Vlahov D, Manini AF. Risk factors for severe respiratory depression from prescription opioid overdose. Addiction. 2018 Jan;113(1):59-66.