title: A Bolus and Bolus Followed by Infusion Study of AZD3043, an Investigational Intravenous Drug for Sedation and Anesthesia: Safety and Pharmacodynamics in Healthy Male and Female Volunteers.
abstract: BACKGROUND
  AZD3043 (THRX-918661) is an investigational phenylpropanoid sedative/anesthetic that is rapidly metabolized by esterases in blood and liver. In the first-in-man study, a 30-minute constant IV infusion of AZD3043 induced anesthesia without major safety or tolerability concerns and with rapid recovery characteristics.
  
  
  METHODS
  The primary objective of this phase 1, single-center, open-label study (clinicaltrials.gov NCT00984880) was to evaluate the safety and tolerability of AZD3043 administered as a single IV bolus and as a bolus followed by infusion. Secondary objectives included evaluation of AZD3043 pharmacodynamics and efficacy. Sequential ascending dose cohorts of 8 healthy volunteers aged 18 to 65 years received either a single 1-minute bolus IV infusion (part A) or a 1-minute bolus followed by a 30-minute infusion (part B). Assessments included adverse events, vital signs, blood gases, laboratory values, clinical signs of sedation/anesthesia, and bispectral index score.
  
  
  RESULTS
  Seventy-two subjects (8 females, 64 males) received AZD3043 doses of 1, 1.5, 2, 4, and 6 mg/kg bolus over 1 minute (part A) or 0.8 + 10, 1 + 15, 3 + 30, and 4 + 40 mg/kg bolus + mg/kg/h infusion for 30 minutes (part B). There were no discontinuations. Adverse events occurring in >1 subject were headache (n = 15; 21%), nausea (n = 7; 10%), vomiting (n = 3; 4%), and fatigue (n = 2; 3%). Twenty-one subjects experienced at least 1 adverse event. There seemed to be no dose relationship associated with any adverse event. Ventilation was maintained, but there was a dose-dependent increase in heart rate. There were no spontaneous reports of pain on injection. Thirty-two subjects were anesthetized, including all subjects in the highest dose group in part A and all subjects in the 2 highest dose groups in part B. Recovery from anesthesia was rapid, with swift return of orientation and proprioception. All subjects were able to walk 10 m without support at their first assessment, 30 minutes after end of dosing, except for 1 subject in each of the 2 mg/kg bolus (part A) and 4 mg/kg bolus + 40 mg/kg/h 30-minute infusion (part B) dose groups, who passed this test at the subsequent assessment, 45 minutes after the end of dosing. Involuntary movements were observed at higher doses, accompanied by increased muscle tone.
  
  
  CONCLUSIONS
  AZD3043 provided rapid recovery from anesthesia with maintained ventilation. Further studies are warranted in a clinical setting.
authors.affiliation: From the Department of Clinical Science Intervention and Technology, Karolinska Institutet, Stockholm at Department of Anesthesiology and Intensive Care, Karolinska University Hospital, Huddinge, Sweden; AstraZeneca US, Wilmington, Delaware; Quantitative Clinical Pharmacology, AstraZeneca R&D, Södertälje, Sweden; Pharmetheus AB, Uppsala, Sweden; and AstraZeneca R&D, Södertälje, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Norberg
authors.forename: Pauline
authors.initials: P
authors.lastname: Koch
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kanes
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Björnsson
authors.forename: Stéphane
authors.initials: S
authors.lastname: Barassin
authors.forename: Kjell
authors.initials: K
authors.lastname: Ahlén
authors.forename: Sigridur
authors.initials: S
authors.lastname: Kalman
mesh_terms: D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D015507:Drugs, Investigational / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D005500:Follow-Up Studies; D006261:Headache / Q000139:chemically induced; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D010648:Phenylacetates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: C573579:AZD-3043; D015507:Drugs, Investigational; D006993:Hypnotics and Sedatives; D010648:Phenylacetates