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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

(2017) ANESTHESIOLOGY. 127(1). p.20-35
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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.
Keywords
VS. SEQUENTIAL-ANALYSIS, ETOMIDATE, PROPOFOL, ANESTHESIA, VOLUNTEERS, PERFORMANCE, INDUCTION, MYOCLONUS, INFUSION, STATE

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Chicago
Struys, Michel, Beatrijs I Valk, Douglas J Eleveld, Anthony R Absalom, Peter Meyer, Sascha Meier, Izaak den Daas, et al. 2017. “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.” Anesthesiology 127 (1): 20–35.
APA
Struys, M., Valk, B. I., Eleveld, D. J., Absalom, A. R., Meyer, P., Meier, S., den Daas, I., et al. (2017). 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. ANESTHESIOLOGY, 127(1), 20–35.
Vancouver
1.
Struys M, Valk BI, Eleveld DJ, Absalom AR, Meyer P, Meier S, et al. 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. ANESTHESIOLOGY. 2017;127(1):20–35.
MLA
Struys, Michel et al. “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.” ANESTHESIOLOGY 127.1 (2017): 20–35. Print.
@article{8532516,
  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.},
  author       = {Struys, Michel and Valk, Beatrijs I and Eleveld, Douglas J and Absalom, Anthony R and Meyer, Peter and Meier, Sascha and den Daas, Izaak and Chou, Thomas and van Amsterdam, Kai and Campagna, Jason A and Sweeney, Steven P},
  issn         = {0003-3022},
  journal      = {ANESTHESIOLOGY},
  keywords     = {VS. SEQUENTIAL-ANALYSIS,ETOMIDATE,PROPOFOL,ANESTHESIA,VOLUNTEERS,PERFORMANCE,INDUCTION,MYOCLONUS,INFUSION,STATE},
  language     = {eng},
  number       = {1},
  pages        = {20--35},
  title        = {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},
  url          = {http://dx.doi.org/10.1097/ALN.0000000000001662},
  volume       = {127},
  year         = {2017},
}

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