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
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;127(1):20-35. doi: 10.1097/ALN.0000000000001662.
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.
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.
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.
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.
环丙基 - 甲氧基羰基依托咪酯（ABP - 700）是一种新型的“软”依托咪酯类似物。这项首次人体研究的主要目的是描述ABP - 700的安全性和有效性，并确定其最大耐受剂量。次要目的是表征ABP - 700及其主要代谢产物（环丙基 - 甲氧基羰基酸）的药代动力学，评估ABP - 700的临床效果，并研究剂量反应以及药代动力学/药效动力学关系。
60名受试者被分为10个队列，接受递增的单次推注ABP - 700或安慰剂。通过临床实验室评估、输液部位反应、生命体征连续监测、体格检查、不良事件监测和促肾上腺皮质激素刺激试验来评估安全性。通过改良的观察者警觉/镇静评估和脑电双频指数监测来评估临床效果。计算药代动力学参数。
在1.00mg/kg剂量时达到停药标准。未报告严重不良事件。不良事件呈剂量依赖性，包括不自主肌肉运动、心动过速和通气效应。促肾上腺皮质激素刺激在所有受试者中均引起生理性皮质醇反应，与安慰剂无差异。药代动力学呈剂量比例关系。三室药代动力学模型能很好地描述数据。推注给药后观察到麻醉/镇静起效迅速，恢复也迅速。针对改良的观察者警觉/镇静评估和脑电双频指数描述了定量的浓度 - 效应关系。
这项ABP - 700的首次人体研究表明，单次推注剂量高达1.00mg/kg时，ABP - 700安全且耐受性良好。发现0.25和0.35mg/kg的推注剂量在临床效果与副作用方面最为有益。
