AQUAVAN Injection Research Articles

Comparative canine Pharmacokinetics–Pharmacodynamics of Fospropofol Disodium Injection, Propofol Eemulsion, and Cyclodextrin-Enabled Propofol Solution Following Bolus Parenteral Administration

The pharmacokinetics and pharmacodynamics of fospropofol (FP) disodium injection, propofol emulsion (PE), and cyclodextrin-enabled propofol (CDP) solution following bolus parenteral administration in dogs was evaluated. Three healthy male beagle dogs were treated in a three-way cross-over study (14 day washout period) with 6 mg/kg propofol equivalents. Blood samples were collected predose and at 16 points postdose through 1440 min and analyzed for propofol and FP, when appropriate. From 5 min predose to 30 min postdose, brain electrical activity [electroencephalography (EEG)] was recorded and analyzed by power spectrum analysis techniques. Each formulation appeared to be well tolerated with transient discomfort observed in the PE and CDP animals and minor excitability in the FP animals prior to loss of consciousness. Blood propofol followed three-compartment pharmacokinetic behavior and derived parameters were not statistically different except for elimination half-life from the CDP formulation and onset, and duration of anesthesia from the FP formulation. The effect site concentrations at 50% the maximum EEG effect for the FP and CDP formulations were approximately one-half that of the PE formulation. Onset and duration of anesthesia are correlated with modeled effect site propofol concentrations. The implications of formulation on pain on injection and propofol activity are discussed.

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: Retraction

An analytical propofol assay inaccuracy was discovered after initial studies on the pharmacokinetics/pharmacodynamics and tolerability of fospropofol had been published. This assay inaccuracy makes the measured propofol plasma concentrations in the following previously published studies unreliable, and therefore these articles are retracted in their entirety:Reference Struys MM, Vanluchene AL, Gibiansky E, Gibiansky L, Vornov J, Mortier EP, Van Bortel L: 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. Anesthesiology 2005; 103:730–43

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: Retraction

An analytical propofol assay inaccuracy was discovered after initial studies on the pharmacokinetics/pharmacodynamics and tolerability of fospropofol had been published. This assay inaccuracy makes the measured propofol plasma concentrations in the following previously published studies unreliable, and therefore these articles are retracted in their entirety:Reference Struys MM, Vanluchene AL, Gibiansky E, Gibiansky L, Vornov J, Mortier EP, Van Bortel L: 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. Anesthesiology 2005; 103:730–43

AQUAVAN Injection, a Water-soluble Prodrug of Propofol, as a Bolus Injection: A Phase I Dose-escalation Comparison with DIPRIVAN (Part 1): Pharmacokinetics: Retraction

AQUAVAN Injection, a Water-soluble Prodrug of Propofol, as a Bolus Injection: A Phase I Dose-escalation Comparison with DIPRIVAN (Part 1): Pharmacokinetics: Retraction

AQUAVAN Injection, a Water-soluble Prodrug of Propofol, as a Bolus Injection: A Phase I Dose-escalation Comparison with DIPRIVAN (Part 1): Pharmacokinetics: Retraction

AQUAVAN Injection, a Water-soluble Prodrug of Propofol, as a Bolus Injection: A Phase I Dose-escalation Comparison with DIPRIVAN (Part 1): Pharmacokinetics: Retraction

Pharmacokinetic and Pharmacodynamic Characteristics of??Medications Used for Moderate Sedation

The ability to deliver safe and effective moderate sedation is crucial to the ability to perform invasive procedures. Sedative drugs should have a quick onset of action, provide rapid and clear-headed recovery, and be easy to administer and monitor. A number of drugs have been demonstrated to provide effective sedation for outpatient procedures but since each agent has its own limitations, a thorough knowledge of the available drugs is required to choose the appropriate drug, dose and/or combination regimen for individual patients. Midazolam, propofol, ketamine and sevoflurane are the most frequently used agents, and all have a quick onset of action and rapid recovery. The primary drawback of midazolam is the potential for accumulation of the drug, which can result in prolonged sedation and a hangover effect. The anaesthetics propofol and sevoflurane have recently been used for sedation in procedures of short duration. Although effective, these agents require monitored anaesthesia care. Ketamine is an effective agent, particularly in children, but there is concern regarding emergence reactions. AQUAVAN injection (fospropofol disodium), a phosphorylated prodrug of propofol, is an investigational agent possessing a unique and distinct pharmacokinetic and pharmacodynamic profile. Compared with propofol emulsion, AQUAVAN is associated with a slightly longer time to peak effect and a more prolonged pharmacodynamic effect. Advances in the delivery of sedation, including the development of new sedative agents, have the potential to further improve the provision of moderate sedation for a variety of invasive procedures.

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: Retracted

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). 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. 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. 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.

AQUAVAN® Injection, a Water-soluble Prodrug of Propofol, as a Bolus Injection: A Phase I Dose-escalation Comparison with DIPRIVAN® (Part 1): Pharmacokinetics: Retracted

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). 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. 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. 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.

Pharmacokinetics and pharmacodynamics of the new propofol prodrug GPI 15715 in rats.

We studied the pharmacokinetics and pharmacodynamics of GPI 15715 (Aquavan injection), a new water-soluble prodrug metabolized to propofol by hydrolysis. Nine adult male Sprague-Dawley rats (398 +/- 31 g) received a bolus dose of 40 mg GPI 15715. The plasma concentrations of GPI 15715 and propofol were determined from arterial blood samples, and the pharmacokinetics of both compounds were investigated using compartment models whereby the elimination from the central compartment of GPI 15715 was used as drug input for the central compartment of propofol. Pharmacodynamics were assessed using the median frequency of the EEG power spectrum. A maximum propofol concentration of 7.1 +/- 1.7 microg mL(-1) was reached 3.7 +/- 0.2 min after bolus administration. Pharmacokinetics were best described by two-compartment models. GPI 15715 showed a short half-life (2.9 +/- 0.2 and 23.9 +/- 9.9 min), an elimination rate constant of 0.18 +/- 0.01 min(-1) and a central volume of distribution of 0.25 +/- 0.02 L kg(-1). For propofol, the half-life was 1.9 +/- 0.1 and 45 +/- 7 min, the elimination rate constant was 0.15 +/- 0.02 min(-1) and the central volume of distribution was 2.3 +/- 0.6 L kg(-1). The maximum effect on the electroencephalogram (EEG)--EEG suppression for >4 s--occurred 6.5 +/- 1.2 min after bolus administration and baseline values of the EEG median frequency were regained 30 min later. The EEG effect could be described by a sigmoid Emax model including an effect compartment (E0 = 16.9 +/- 7.9 Hz, EC50 = 2.6 +/- 0.8 microg mL(-1), ke0 = 0.35 +/- 0.04 min(-1)). Compared with known propofol formulations, propofol from GPI 15715 showed a longer half-life, an increased volume of distribution, a delayed onset, a sustained duration of action and a greater potency with respect to concentration.

A Randomized, Open-Label, Multicenter, Dose-Ranging Study of Sedation with Aquavan Injection (GPI 15715) During Colonoscopy

A Randomized, Open-Label, Multicenter, Dose-Ranging Study of Sedation with Aquavan Injection (GPI 15715) During Colonoscopy