AQUAVAN injection, a water-soluble prodrug of propofol, as a bolus injection: a phase I dose-escalation comparison with DIPRIVAN (part 1): pharmacokinetics.
BACKGROUND
AQUAVAN Injection (AQ) (GPI 15715; Guilford Pharmaceutical Inc., Baltimore, MD) is a water-soluble prodrug of propofol (PropofolGPI). This study aimed to explore the pharmacokinetics of AQ, PropofolGPI, and formate (a metabolite of AQ) and to compare them with the pharmacokinetics of propofol lipid emulsion (PropofolD).


METHODS
After ethics committee approval, 36 healthy volunteers were randomly allocated into six cohorts (male/female: 3/3) and given a single bolus of AQ (5, 10, 15, 20, 25, or 30 mg/kg). For comparison, an equipotent dose (as measured by the Bispectral Index) of PropofolD was given to the same subjects 1 week later. For both drugs, blood samples were collected (1-480 min) to analyze AQ, PropofolGPI, PropofolD, and formate concentrations. Noncompartmental pharmacokinetic analyses were performed for all analytes. A population compartmental model was developed for AQ and PropofolGPI using NONMEM. The models were evaluated using simulations and bootstraps.


RESULTS
The noncompartmental pharmacokinetic comparison revealed different dispositions of PropofolGPI and PropofolD. The maximum plasma concentration was lower for PropofolGPI than for PropofolD at equipotent doses, and apparent clearance and distribution volume were much higher for PropofolGPI than for PropofolD. Formate concentrations were similar when injecting both drugs and were not higher than baseline. Compartmental modeling revealed that the pharmacokinetic behavior of AQ and its liberated PropofolGPI was best described by a nonlinear, six-compartment model, composed of two three-compartment models connected to each other by hydrolysis of AQ to PropofolGPI.


CONCLUSIONS
PropofolGPI showed different noncompartmental pharmacokinetics from PropofolD, hereby revealing the influence of the formulation. The combined model for AQ and PropofolGPI was best modeled by a nonlinear, six-compartment model.
Gibiansky
Ekaterina
E
Clinical Research, Guilford Pharmaceuticals Inc., Baltimore, Maryland, USA.
Struys
Michel M R F
MM
Gibiansky
Leonid
L
Vanluchene
Ann L G
AL
Vornov
James
J
Mortier
Eric P
EP
Burak
Eric
E
Van Bortel
Luc
L
D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015742:Propofol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
D011355:Prodrugs; C472965:fospropofol; D015742:Propofol