title: Pharmacokinetics and clinical pharmacodynamics of the new propofol prodrug GPI 15715 in volunteers.
abstract: BACKGROUND
  GPI 15715 (AQUAVAN injection) is a new water-soluble prodrug which is hydrolyzed to release propofol. The objectives of this first study in humans were to investigate the safety, tolerability, pharmacokinetics, and clinical pharmacodynamics of GPI 15715.
  
  
  METHODS
  Three groups of three healthy male volunteers (aged 19-35 y, 67-102 kg) received 290, 580, and 1,160 mg GPI 15715 as a constant rate infusion over 10 min. The plasma concentrations of GPI 15715 and propofol were measured from arterial and venous blood samples up to 24 h. Pharmacokinetics were analyzed with compartment models. Pharmacodynamics were assessed by clinical signs.
  
  
  RESULTS
  GPI 15715 was well tolerated without pain on injection. Two subjects reported a transient unpleasant sensation of burning or tingling at start of infusion. Loss of consciousness was achieved in none with 290 mg and in one subject with 580 mg. After 1,160 mg, all subjects experienced loss of consciousness at propofol concentrations of 2.1 +/- 0.6 microg/ml. A two-compartment model for GPI 15715 (central volume of distribution, 0.07 l/kg; clearance, 7 ml. kg-1 min-1; terminal half-life, 46 min) and a three-compartment model for propofol (half-lives: 2.2, 20, 477 min) best described the data. The maximum decrease of blood pressure was 25%; the heart rate increased by approximately 35%. There were no significant laboratory abnormalities.
  
  
  CONCLUSIONS
  Compared with propofol lipid emulsion, the potency seemed to be higher with respect to plasma concentration but was apparently less with respect to dose. Pharmacokinetic simulations showed a longer time to peak propofol concentration after a bolus dose and a longer context-sensitive half-time.
authors.affiliation: Department of Anesthesiology, University of Erlangen-Nuremberg, Erlangen, Germany. joerg.fechner@kfa.imed.uni-erlangen.de
authors.forename: Jörg
authors.initials: J
authors.lastname: Fechner
authors.forename: Harald
authors.initials: H
authors.lastname: Ihmsen
authors.forename: Dirk
authors.initials: D
authors.lastname: Hatterscheid
authors.forename: Christine
authors.initials: C
authors.lastname: Schiessl
authors.forename: James J
authors.initials: JJ
authors.lastname: Vornov
authors.forename: Eric
authors.initials: E
authors.lastname: Burak
authors.forename: Helmut
authors.initials: H
authors.lastname: Schwilden
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schüttler
mesh_terms: D000328:Adult; D000771:Anesthesia, Intravenous; D018686:Anesthetics, Intravenous / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D003243:Consciousness / Q000187:drug effects; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008954:Models, Biological; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015742:Propofol / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015656:Respiratory Mechanics / Q000187:drug effects
chemical_list: D018686:Anesthetics, Intravenous; D011355:Prodrugs; C472965:fospropofol; D015742:Propofol