AQUAVAN injection, a water-soluble prodrug of propofol, as a bolus injection: a phase I dose-escalation comparison with DIPRIVAN (part 2): pharmacodynamics and safety.
BACKGROUND
AQUAVAN Injection (AQ) (GPI 15715; Guilford Pharmaceuticals Inc., Baltimore, MD) is a water-soluble prodrug of propofol. The authors explored the pharmacodynamics and safety of AQ and compared it with propofol lipid emulsion (PropofolD).


METHODS
After institutional review board approval, 36 volunteers with American Society of Anesthesiologists physical status of I were randomly allocated into six cohorts (male/female: 3/3 per cohort) and given a single bolus of AQ (5, 10, 15, 20, 25, or 30 mg/kg). A Bispectral Index monitor (Aspect Medical Systems Inc., Newton, MA) measured the hypnotic effect. The lowest Bispectral Index level (BISpeak) was recorded. One week later, PropofolD was given to the same subjects at 50 mg/min to reach a similar BISpeak. Heart rate, oxygen saturation measured by pulse oximetry, blood pressure, and side effects were monitored. Incidence and duration of apnea and loss (LOCverbal) and return of response to verbal command were measured. A population compartmental pharmacokinetic-pharmacodynamic model was developed for AQ using NONMEM and evaluated using simulations, leverage, and bootstrap analyses.


RESULTS
In the higher dosages (cohorts 4-6), all subjects achieved LOCverbal. Similar times until LOCverbal were seen for AQ and PropofolD. A dose-related increase in duration of LOCverbal was longer for AQ than for PropofolD. AQ BISpeak occurred later than with PropofolD. Pain on injection was only present with PropofolD (12 of 36). With AQ, transient paresthesias and pruritus were seen. Hemodynamic profiles were similar for both drugs, except for an initial tachycardia after AQ administration. Dose-dependent apnea was more pronounced with PropofolD than with AQ. The AQ combined pharmacokinetic-pharmacodynamic profile was best described by a nonlinear, six-compartment pharmacokinetic model and an effect site compartment. A dependency of the ke0 value on the PropofolGPI plasma concentration was noted.


CONCLUSIONS
Bolus administration of AQ achieves LOCverbal at a similar time as an equipotent amount of PropofolD but shows a longer time to BISpeak and prolonged pharmacodynamics. For both drugs, excellent drug safety was achieved, although there was a tendency of fewer and shorter duration of apneas for AQ.
Struys
Michel M R F
MM
Department of Anesthesia, Ghent University Hospital, Ghent, Belgium.
Vanluchene
Ann L G
AL
Gibiansky
Ekaterina
E
Gibiansky
Leonid
L
Vornov
James
J
Mortier
Eric P
EP
Van Bortel
Luc
L
D000293:Adolescent; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D015742:Propofol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology*
D011355:Prodrugs; C472965:fospropofol; D015742:Propofol