Newly Published
Perioperative Medicine  |   May 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
Author Notes
  • 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.).
  • Timothy Brennan, Ph.D., M.D., served as Handling Editor for this article. M.M.R.F.S. and B.I.V. contributed equally to this article and should both be considered as first authors. Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Timothy Brennan, Ph.D., M.D., served as Handling Editor for this article. M.M.R.F.S. and B.I.V. contributed equally to this article and should both be considered as first authors. Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Submitted for publication March 1, 2016. Accepted for publication March 27, 2017.
    Submitted for publication March 1, 2016. Accepted for publication March 27, 2017.×
  • Acknowledgments: The authors acknowledge the support of Rob Spanjersberg, C.N., C.R.C., Clinical Research Coordinator, and Anne-Sophia Koene, M.D., Research Fellow (Department of Anesthesiology, University Medical Center Groningen, The Netherlands); Khalid Abd-Elaziz, M.D., Research Physician, Wouter Dijkstra, Pharm.D., Clinical Trial Pharmacist, Gonda Renkema, B.Sc., Clinical Study Coordinator, and Mariska Beukers, M.Sc., Project Manager (QPS Netherlands, BV, Groningen, The Netherlands); David Grayzel, M.D. (CEO, Annovation Biopharma, Cambridge, now Partner, Atlas Venture, Cambridge, Massachusetts); Kevin Pojasek, Ph.D. (COO, Annovation Biopharma, Cambridge, Massachusetts, now CEO, Quartet Medicine, Cambridge, Massachusetts); Scott Chappel, Ph.D. (CSO, Annovation Biopharma, Cambridge, Massachusetts, now CSO, Surface Oncology, Cambridge, Massachusetts); Amy DiRico, B.S. (Clinical Project Director, Phase One, LLC, Norwich, Connecticut); and Chau Hwei Fu, Ph.D. (Global PK Head, QPS LLC, Newark, Delaware) during the trial and the preparation of the manuscript.
    Acknowledgments: The authors acknowledge the support of Rob Spanjersberg, C.N., C.R.C., Clinical Research Coordinator, and Anne-Sophia Koene, M.D., Research Fellow (Department of Anesthesiology, University Medical Center Groningen, The Netherlands); Khalid Abd-Elaziz, M.D., Research Physician, Wouter Dijkstra, Pharm.D., Clinical Trial Pharmacist, Gonda Renkema, B.Sc., Clinical Study Coordinator, and Mariska Beukers, M.Sc., Project Manager (QPS Netherlands, BV, Groningen, The Netherlands); David Grayzel, M.D. (CEO, Annovation Biopharma, Cambridge, now Partner, Atlas Venture, Cambridge, Massachusetts); Kevin Pojasek, Ph.D. (COO, Annovation Biopharma, Cambridge, Massachusetts, now CEO, Quartet Medicine, Cambridge, Massachusetts); Scott Chappel, Ph.D. (CSO, Annovation Biopharma, Cambridge, Massachusetts, now CSO, Surface Oncology, Cambridge, Massachusetts); Amy DiRico, B.S. (Clinical Project Director, Phase One, LLC, Norwich, Connecticut); and Chau Hwei Fu, Ph.D. (Global PK Head, QPS LLC, Newark, Delaware) during the trial and the preparation of the manuscript.×
  • Research Support: This study was a sponsor-initiated study by The Medicines Company, Parsippany, New Jersey. The sponsor covered the costs related to this study.
    Research Support: This study was a sponsor-initiated study by The Medicines Company, Parsippany, New Jersey. The sponsor covered the costs related to this study.×
  • Competing Interests: Dr. Struys: his research group/department received grants and funding from The Medicines Company (Parsippany, New Jersey), Masimo (Irvine, California), Fresenius (Bad Homburg, Germany), Acacia Design (Maastricht, The Netherlands), Medtronic (Dublin, Ireland), and honoraria from The Medicines Company, Masimo, Fresenius, Baxter (Deerfield, Illinois), Medtronic, and Demed Medical (Temse, Belgium). Dr. Absalom: his research group/department received grants and funding from The Medicines Company, Masimo, Fresenius, Acacia Design, Medtronic, and he has received honoraria from The Medicines Company and Janssen Pharmaceutica NV (Beerse, Belgium). Dr. Meyer attended one advisory board from The Medicines Company, for which his department received an honorarium. Dr. Meier received honoraria from Abbott Vascular (Hoofddorp, The Netherlands). He also attended one advisory board from The Medicines Company, for which his department received an honorarium. Dr. Daas is an employee of QPS Netherlands, BV, Groningen, The Netherlands. Dr. Chou is an employee of QPS LLC, Newark, Delaware. Dr. Campagna is an employee of The Medicines Company. Mr. Sweeney is an employee of The Medicines Company and former employee of Annovation Biopharma (Cambridge, Massachusetts). The other authors declare no competing interests.
    Competing Interests: Dr. Struys: his research group/department received grants and funding from The Medicines Company (Parsippany, New Jersey), Masimo (Irvine, California), Fresenius (Bad Homburg, Germany), Acacia Design (Maastricht, The Netherlands), Medtronic (Dublin, Ireland), and honoraria from The Medicines Company, Masimo, Fresenius, Baxter (Deerfield, Illinois), Medtronic, and Demed Medical (Temse, Belgium). Dr. Absalom: his research group/department received grants and funding from The Medicines Company, Masimo, Fresenius, Acacia Design, Medtronic, and he has received honoraria from The Medicines Company and Janssen Pharmaceutica NV (Beerse, Belgium). Dr. Meyer attended one advisory board from The Medicines Company, for which his department received an honorarium. Dr. Meier received honoraria from Abbott Vascular (Hoofddorp, The Netherlands). He also attended one advisory board from The Medicines Company, for which his department received an honorarium. Dr. Daas is an employee of QPS Netherlands, BV, Groningen, The Netherlands. Dr. Chou is an employee of QPS LLC, Newark, Delaware. Dr. Campagna is an employee of The Medicines Company. Mr. Sweeney is an employee of The Medicines Company and former employee of Annovation Biopharma (Cambridge, Massachusetts). The other authors declare no competing interests.×
  • Reproducible Science: Full protocol available at: m.m.r.f.struys@umcg.nl. Raw data available at: m.m.r.f.struys@umcg.nl.
    Reproducible Science: Full protocol available at: m.m.r.f.struys@umcg.nl. Raw data available at: m.m.r.f.struys@umcg.nl.×
  • Correspondence: Address correspondence to Dr. Struys: Department of Anesthesiology, University of Groningen, University Medical Center Groningen, P.O. Box 30001, 9700 RB Groningen, The Netherlands. m.m.r.f.struys@umcg.nl. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Pharmacology
Perioperative Medicine   |   May 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 Newly Published on May 4, 2017. doi:10.1097/ALN.0000000000001662
Anesthesiology Newly Published on May 4, 2017. doi:10.1097/ALN.0000000000001662
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.

Abstract

TOC Statement: In a first-in-human study, ABP-700 was safe and well tolerated up to a maximum tolerated bolus dose of 1.0 mg/kg. Onset of hypnosis after bolus administration was rapid as was recovery. APB-700 did not cause cardiovascular depression, centrally induced respiratory depression, or suppression of the physiologic response of the adrenal axis to adrenocorticotropic hormone stimulation. Involuntary muscle movements were observed at doses of 0.175 mg/kg and greater.