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

• Published in: Anesthesiology (Philadelphia) 2017-07, Vol.127 (1), p.20-35
• Main Authors: Struys, Michel M. R F, Valk, Beatrijs I, Eleveld, Douglas J, Absalom, Anthony R, Meyer, Peter, Meier, Sascha, den Daas, Izaak, Chou, Thomas, van Amsterdam, Kai, Campagna, Jason A, Sweeney, Steven P
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Dose-Response Relationship, Drug; Double-Blind Method; Etomidate - administration & dosage; Etomidate - analogs & derivatives; Etomidate - pharmacology; Female; Humans; Hypnotics and Sedatives - administration & dosage; Hypnotics and Sedatives - pharmacology; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Reference Values; Young Adult
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/ALN.0000000000001662

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.