Comparative pharmacokinetics and pharmacodynamics of the new propofol prodrug GPI 15715 and propofol emulsion.
BACKGROUND
GPI 15715 is a new water-soluble prodrug that is hydrolyzed to release propofol. The objectives of this crossover study in volunteers were to investigate the pharmacokinetics and pharmacodynamics of GPI 15715 in comparison with propofol emulsion.


METHODS
In two separate sessions, nine healthy male volunteers (19-35 yr, 70-86 kg) received GPI 15715 and propofol emulsion as a target controlled infusion over 60 min. In the first 20 min, the propofol target concentration increased linearly to 5 microg/ml. Subsequently, the targets were reduced to 3 microg/ml and 1.5 microg/ml for 20 min each. The plasma concentrations of GPI 15715 and propofol were measured from arterial and venous blood samples up to 24 h and pharmacokinetics were analyzed. The pharmacodynamic effect was measured by the median frequency of the power spectrum of the electroencephalogram, and a sigmoid model with effect compartment was fitted to the data.


RESULTS
Compared with propofol emulsion, propofol from GPI 15715 showed a different disposition function and especially larger volumes of distribution. The propofol effect site concentration for half maximum effect was 2.0 +/- 0.5 microg/ml for GPI 15715 and 3.0 +/- 0.7 microg/ml for propofol emulsion (P < 0.05). Propofol from GPI 15715 did not show a hysteresis between plasma concentration and effect.


CONCLUSIONS
Compared with propofol emulsion, propofol from GPI 15715 showed different pharmacokinetics and pharmacodynamics, particularly a higher potency with respect to concentration. These differences may indicate an influence of the formulation.
Fechner
Jörg
J
Department of Anesthesiology, University of Erlangen-Nuremberg, Germany. Joerg.Fechner@kfa.imed.uni-erlangen.de
Ihmsen
Harald
H
Hatterscheid
Dirk
D
Jeleazcov
Christian
C
Schiessl
Christine
C
Vornov
James J
JJ
Schwilden
Helmut
H
Schüttler
Jürgen
J
D000328:Adult; D000465:Algorithms; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D004569:Electroencephalography / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D015233:Models, Statistical; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015742:Propofol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012890:Sleep / Q000187:drug effects
D018686:Anesthetics, Intravenous; D011355:Prodrugs; C472965:fospropofol; D015742:Propofol