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) Vol. 127; no. 1; pp. 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: Journal Article
• Language: English
• Published: United States Copyright by , the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc 01.07.2017
• 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; 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.