AQUAVAN (R) injection, a water-soluble prodrug of propofol as a bolus injection: A phase I dose-escalation comparison with DIPRIVAN (R) (Part 2) - Pharmacodynamics and safety (Retracted article. See vol. 112, pg. 1058, 2010)

MMRF Struys*, ALG Vanluchene, E Gibiansky, L Gibiansky, J Vornov, EP Mortier, L Van Bortel

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

44 Citations (Scopus)

Abstract

Background: AQUAVAN((R)) 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 (Propofol(D)).

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((R)) monitor (Aspect Medical Systems Inc., Newton, MA) measured the hypnotic effect. The lowest Bispectral index level (BISpeak) was recorded. One week later, Propofol, 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-pharniacodynamic model was developed for AQ using NONMEM and evaluated using simulations, leverage, and boot strap analyses.

Results: In the higher dosages (cohorts 4-6), all subjects achieved LOCverbal. Similar times until LOCverbal were seen for AQ and Propofol(D). A dose-related increase in duration of LOCverbal was longer for AQ than for PropofolD. AQ BISpeak occurred later than with Propofol(D). Pain on injection was only present with Propofol(D) (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 Propofol, 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 k(e0) value on the Propofol(GFI) plasma concentration was noted.

Conclusion: Bolus administration of AQ achieves LOCverbal at a similar time as an equipotent amount of Propofol(D) 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.

Original languageEnglish
Pages (from-to)730-743
Number of pages14
JournalAnesthesiology
Volume103
Issue number4
Publication statusPublished - Oct-2005
Externally publishedYes
EventAnnual Meeting of the Association-of-Anesthesiologists - Orlando, United Kingdom
Duration: 12-Oct-200216-Oct-2002

Keywords

  • BISPECTRAL INDEX
  • PHARMACOKINETICS
  • FOSPHENYTOIN
  • PHARMACOLOGY
  • GPI-15715
  • SEDATION
  • INFUSION
  • EEG

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