• Michel M R F Struys, Beatrijs I Valk, Douglas J Eleveld, Anthony R Absalom, Peter Meyer, Sascha Meier, Izaak den Daas, Thomas Chou, Kai van Amsterdam, Jason A Campagna, and Steven P Sweeney.
• From the Department of Anesthesiology, University of Groningen, University Medical Center Groningen, The Netherlands (M.M.R.F.S., B.I.V., D.J.E., A.R.A., P.M., S.M., K.v.A.); Department of Anesthesia and Perioperative Medicine, Ghent University, Gent, Belgium (M.M.R.F.S.); QPS Netherlands, BV, Groningen, The Netherlands (I.d.D.); QPS LLC, Newark, Delaware (T.C.); and The Medicines Company, Parsippany, New Jersey (J.A.C., S.P.S.).
• Anesthesiology. 2017 Jul 1; 127 (1): 20-35.

BackgroundCyclopropyl-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.MethodsSixty 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.ResultsStopping 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.ConclusionsThis 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.

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