A Phase 1, Single-center, Double-blind, Placebo-controlled Study in Healthy Subjects to Assess the Safety, Tolerability, Clinical Effects, and Pharmacokinetics–Pharmacodynamics of Intravenous Cyclopropyl-methoxycarbonylmetomidate (ABP-700) after a Single Ascending Bolus Dose

Abstract

Background Cyclopropyl-methoxycarbonylmetomidate (ABP-700) is a new “soft” etomidate analog. The primary objectives of this first-in-human study were to describe the safety and efficacy of ABP-700 and to determine its maximum tolerated dose. Secondary objectives were to characterize the pharmacokinetics of ABP-700 and its primary metabolite (cyclopropyl-methoxycarbonyl acid), to assess the clinical effects of ABP-700, and to investigate the dose–response and pharmacokinetic/pharmacodynamic relationships. Methods Sixty subjects were divided into 10 cohorts and received an increasing, single bolus of either ABP-700 or placebo. Safety was assessed by clinical laboratory evaluations, infusion-site reactions, continuous monitoring of vital signs, physical examination, adverse event monitoring, and adrenocorticotropic hormone stimulation testing. Clinical effects were assessed with modified observer’s assessment of alertness/sedation and Bispectral Index monitoring. Pharmacokinetic parameters were calculated. Results Stopping criteria were met at 1.00 mg/kg dose. No serious adverse events were reported. Adverse events were dose-dependent and comprised involuntary muscle movement, tachycardia, and ventilatory effects. Adrenocorticotropic hormone stimulation evoked a physiologic cortisol response in all subjects, no different from placebo. Pharmacokinetics were dose-proportional. A three-compartment pharmacokinetic model described the data well. A rapid onset of anesthesia/sedation after bolus administration and also a rapid recovery were observed. A quantitative concentration–effect relationship was described for the modified observer’s assessment of alertness/sedation and Bispectral Index. Conclusions This first-in-human study of ABP-700 shows that ABP-700 was safe and well tolerated after single-bolus injections up to 1.00 mg/kg. Bolus doses of 0.25 and 0.35 mg/kg were found to provide the most beneficial clinical effect versus side-effect profile.

Safety and clinical effect of i.v. infusion of cyclopropyl-methoxycarbonyl etomidate (ABP-700), a soft analogue of etomidate, in healthy subjects

“…was chosen based on human safety, pharmacokinetic (PK) and pharmacodynamic (PD) data from subjects in the bolus only study. 20 PK data from the maximum tolerated dose (MTD) and highest dose level tested in this study (1000 mg kg À1 ) were used to determine a starting dose where the total exposure over a 30-min infusion would not exceed the total exposure achieved during a 1 min i.v. bolus of 1000 mg kg À1 .…”

“…21 After each cohort, all available data regarding safety, tolerability, PK, and PD were evaluated by the principal investigator (PI), the sponsor, and the ethics committee before proceeding to the next dose. Stopping criteria for further drug escalation were identical to the single-bolus study 20 : Grade 3 or higher dose-limiting toxicity event as defined in the September 2007 Food and Drug Administration Guidance; local injection site reactions that were Grade 2 or higher; bradycardia considered clinically significant; and QTcF (QT interval corrected according to Fridericia) change from baseline >100 ms or total QTcF of >500 ms; SpO 2 <90% not resolved by simple stimulation, jaw thrust, or supplemental oxygen administered via nasal prongs; any serious AEs that were considered by the PI to be related to the study drug; and any clinically significant AEs that the sponsor and PI considered a safety concern.…”

Thiopental to desflurane - an anaesthetic journey. Where are we going next?

“…17 Excitation was frequently reported in experimental anaesthetics which never reached general clinical use and may be present to some degree in the experimental short-acting etomidate derivative ABP-700, which was recently under development. 18 The genesis of anaesthesia induced excitation and seizures remains obscure. 17 19 No reliable preclinical model exists to predict excitation (or the lack of it) by hypnotics.…”

“…The two novel hypnotic compounds have recently been progressed into advanced clinical development, remimazolam 51 and ABP-700 18 were both targeted in the first instance at sedation for gastrointestinal endoscopy. The business opportunity is to replace propofol sedation with a short-acting safe hypnotic suitable for use by non-anaesthetists whilst achieving an improved recovery profile in comparison to midazolam.…”

“…Volunteer (Phase 1) and early clinical trial experience with ABP-700 showed dose-related excitatory effects similar to the parent molecule etomidate. 18 The presence of excitatory effects during human testing prompted additional pre-clinical investigation, which demonstrated seizures in some dogs anaesthetised with ABP-700. Seizures had not been observed in humans and these dog findings may be species-specific.…”