A Phase 1 Dose Optimization Study of Abp-700 with Opiates And/Or Midazolam Pre-Medication in Healthy Adult Volunteers Targeting Induction of General Anesthesia

INTRODUCTION: ABP-700 is a novel, second-generation metabolically labile etomidate analogue in development for procedural sedation and general anesthesia . Pre-clinical and Phase I studies show minimal hemodynamic and respiratory depression, no adrenocortical suppression, and rapid emergence from sedation and anesthesia 1,2 . Like etomidate, ABP-700 is associated with involuntary muscle movement (IMM) that is attenuated with opiate pre-medication 2 . This study aimed to determine a safety, pharmacokinetic, and pharmacodynamic profile of IV bolus and a bolus as infusion dose of ABP-700 when administered after premedication (PM) with ommonly used opiates, midazolam or their combination . METHODS: An open label, Phase I study was performed with ethics approval in accordance with the Declaration of Helsinki . Doses of ABP-700 were selected based on prior Phase I results showing a safety, efficacy and tolerability profile consistent with clinical utility for induction of general anesthesia . All PM was given as IV bolus 5 min prior to ABP-700 . Eighty-Four subjects (50% male), ages 18 to 53, were studied in 10 cohorts: 5 cohorts (n=40) received fentanyl (2 mcg/kg), sufentanil (0 .2 mcg/kg), midazolam (15 or 30 mcg/kg), or midazolam-fentanyl (15 mcg/kg-0 .5 mcg/kg) followed by 0 .25 mg/kg ABP-700; 3 cohorts (n=24) received midazolam (15 or 30 mcg/kg) or midazolam-fentanyl combination followed by 0 .35 mg/kg ABP-700 . One cohort (n=4) received remifentanil infusion (0 .5 mcg/kg/min) for 5 min prior to 0 .25 mg/kg ABP-700 and continued for 5 min thereafter at 0 .25 mcg/kg/min . One cohort (n=16) received fentanyl followed by 0 .7 mg/kg BP-700 given as a 4 min infusion .Safety assessments included clinical labs, hemodynamic, respiratory and adverse event (AE) monitoring . Hypnotic effect was determined with MOAA/S scoring and BIS monitoring . RESULTS: All doses of ABP-700 were well tolerated with good hemodynamic stability . ABP-700 given as bolus effected a mean time to unconsciousness (MOAA/S 0. Most AE’s were reported as mild; one subject experienced moderate IMM .Apnea requiring intervention occurred in 3 subjects given high dose remifentanil; 2 additional subjects had 15 seconds of apnea without need for intervention. CONCLUSIONS: ABP-700 is safe and generally well-tolerated when given with commonly used PM regimens . With the exception of remifentanil, the duration of sedation and safety profile of ABP­700 did not appreciably differ among PM regimens . IMM among all PM combinations was generally mild. Only high dose remifentanil was associated with clinically significant respiratory depression. ABP-700 used in combination with commonly used PMs warrants further investigation of possible clinical utility for deep sedation and induction of general anesthesia . REFERENCES: 1. Anesthesiology 121: 1203 (2014) 2. ASA Annual Meeting 2015 A3012