Water-soluble Prodrug Of Propofol Research Articles

Fospropofol Disodium Is Effective and Safe for Sedation during Colonoscopy

Purpose: Fospropofol disodium (FP), a water-soluble prodrug of propofol, possesses a pharmacokinetic profile characterized by a smooth and predictable rise in propofol plasma concentrations that is unique from its active metabolite, propofol. This double-blind, multicenter, phase 3 study evaluated the safety & efficacy of FP 6.5 mg/kg & 2 mg/kg in patients undergoing colonoscopy. Methods: 314 patients ≥18 years (ASA P1 to P3) were randomized to FP 6.5 mg/kg, FP 2 mg/kg, or midazolam (MD) 0.02 mg/kg in a 3:2:1 allocation following pretreatment with fentanyl 50 mcg. Patients were permitted to receive up to 3 supplemental doses of study drug before being considered a treatment failure & receiving an alternative sedative. Sedation was assessed using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S). The primary endpoint was sedation success, defined by 3 consecutive MOAA/S scores of ≤4 after administration of sedative, and completion of the procedure without use of an alternative sedative medication & without manual/mechanical ventilation. Other endpoints included measures of clinical benefit, recovery, memory retention, patient & physician satisfaction, and safety. Results: Sedation success (87% vs 26%; P < .001) was higher and the requirement for supplemental analgesic medication lower (55% vs 77%; P= .001) in the FP 6.5 mg/kg group than the FP 2 mg/kg group. Patients in the 6.5 mg/kg group were less likely to remember being awake during the procedure (51% vs 100%; P < .0001). The majority of patients in both groups reported willingness to use the sedative again (96% vs 91%). Patients in the FP 6.5 mg/kg group had higher memory retention (67%) than patients in the FP 2 mg/kg group (59%). Mean physician satisfaction scores were higher is the FP 6.5 mg/kg group (7.7) than in the FP 2 mg/kg group (4.5), P < .001. FP was well tolerated, with no serious treatment-related adverse events (TRAEs), deaths, or AE-related procedure discontinuations. The most common TRAEs in the FP 6.5 mg/kg and 2 mg/kg groups were paresthesias (68% vs 60%) and pruritus (16% vs 26%). Six patients experienced transient sedation-related AEs: FP 6.5 mg/kg (hypoxemia [resolved following repeated verbal stimulation, N = 1], hypotension [N = 2]); FP 2 mg/kg (hypotension [N = 2]); midazolam (hypotension). Conclusion: The FP 6.5 mg/kg dosing regimen is safe and effective for sedation during colonoscopy and is associated with a high level of sedation success, patient and physician satisfaction, and clear-headed recovery.

Clinical pharmacodynamics of AQUAVAN® injection - a water soluble prodrug of propofol - compared to lipid formulated propofol for cardiac anaesthesia

1Department of Anaesthesiology, University Hospital of Erlangen, Germany; 2MGI PHARMA, Baltimore, USA

Clinical pharmacodynamics of AQUAVAN® injection, a watersoluble prodrug of propofol, compared to lipid formulated propofol for cardiac anaesthesia

Clinical pharmacodynamics of AQUAVAN® injection, a watersoluble prodrug of propofol, compared to lipid formulated propofol for cardiac anaesthesia

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Drug Interaction Study of Fospropofol Disodium (FD) and Premedications in Healthy, Adult Subjects

Objective: Fospropofol disodium (FD), a water-soluble prodrug of propofol, is an investigational sedative/hypnotic agent for moderate sedation during routine colonoscopy. The primary objective was to estimate the adjustment in cumulative dose of FD required to achieve targeted sedative effect (Modified Observer's Assessment of Alertness/Sedation [MOAA/S] score 3 or less) when preceded by typical pretreatment medications. Methods: This double-blind, randomized, placebo-controlled, phase 1 study evaluated FD in healthy volunteers aged 18-45 years. Subjects were randomized to pretreatment with fentanyl citrate (1 μg/kg), meperidine hydrochloride (0.75 mg/kg), midazolam hydrochloride (0.01 mg/kg), morphine sulfate (0.1 mg/kg), or saline placebo administered intravenously within 5 minutes or 15 minutes (morphine only) before injection of a weight-based, bolus dose of FD (8 mg/kg). Up to 4 supplemental doses of 2 mg/kg FD were administered until targeted MOAA/S of 3 or less was reached. Cumulative and supplemental doses of FD, pharmacodynamics and safety were evaluated. Results: All subjects completed the study. There was no overall effect of premedication on the cumulative dose required to achieve the targeted MOAA/S score of 3 or less (p = 0.098) (see table). FD was well tolerated. Most common overall adverse events (AEs) were burning sensation (46.7%), genital pruritis (16.7%), paresthesia (15.0%), and apnea (6.7%). The highest incidence of apnea occurred in the groups receiving opiates. In addition, the highest observed end tidal CO2 occurred in subjects pretreated with either fentanyl or meperidine. One case of hysterical paralysis in the placebo pretreatment group was reported as a serious AE. Conclusions: Pretreatment with opiates or midazolam did not alter the dosage of FD required to reach target sedation level or the pharmacodynamic profile of FD. There was evidence of respiratory depression from opiate pretreatment drugs. FD can be used safely in conjunction with different pretreatment agents for moderate sedation. Tabled 1Premedication Placebo (saline) N = 12 Fentanyl (1 μg/kg) N = 12 Meperidine (0.75 mg/kg) N = 12 Morphine (0.1 mg/kg) N = 12 Midazolam (0.01 mg/kg) N = 12 Mean cumulative dose of FD (mg/kg) ± SD 9.8 ± 1.3 10.3 ± 2.4 9.3 ± 1.3 11.5 ± 2.6 9.7 ± 2.2 Open table in a new tab

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.

Population Pharmacokinetic Models for Predicting Sedation with GPI 15715 Prodrug of Propofol (AQUAVAN® Injection) for Colonoscopy

Purpose: GPI 15715 (AQUAVANInjection), a novel sedative/hypnotic water-soluble prodrug of propofol with pharmacokinetics (PK) that differ significantly from those of propofol emulsion, provides rapid onset and recovery of anesthesia during colonoscopy. Models relating propofol concentrations to sedation (using Modified Observers Assessment of Alertness/Sedation [MOAA/S] scores) and predicting concentrations of GPI 15715 and derived propofol were constructed from PK and sedation data from a randomized dose-ranging study of AQUAVAN in patients undergoing colonoscopy. Methods: Patients received premedication (fentanyl 11201 g by IV bolus) and initial IV bolus dose of AQUAVAN with up to 4 supplemental doses (total dose = 4951675 mg). Plasma concentrations of GPI 15715 and GPI 15715-derived propofol collected at:1 and 9 min after initial dose; return to MOAA/S score = 5; and discharge. MOAA/S taken every 2 min until patients were fully alert. Data analyzed from 158 patients (approximately 10% >65 years old). Models developed using nonlinear repeated-measures statistical methodology (utilizing NONMEM software). Simulations tested predictive capabilities. Results: Linear 5-compartment model described PK of GPI 15715, propofol, and GPI 15715/propofol concentration delay. Proportional odds model described probabilities of achieving specific MOAA/S scores at different concentrations. Maximum propofol concentration from GPI 15715 predicted at 45 min. Lean body weight was the best predictor of GPI 15715 and propofol concentrations for all body sizes/compositions. Patients >65 years attained same levels of sedation with 25% to 33% lower propofol concentrations compared with younger patients. Premedication had no additive effect on MOAA/S. Simulations demonstrated the models predict sedation levels and time course of sedation for different dosing regimens. Conclusions: Fentanyl premedication did not influence GPI 15715-derived propofol-induced sedation. Older patients may require less AQUAVAN to attain sedation than younger patients. PK and sedation models allow optimization of GPI 15715 dose and dosing regimens for sedation. Safety and efficacy of optimized regimens for GPI 15715-induced sedation with premedication will be tested in a randomized, double-blind, dose-response study in patients undergoing mild-to-moderate (procedural) sedation for colonoscopy. Supported by Guilford Pharmaceuticals Inc.

Sedation with GPI 15715, a Water-Soluble Prodrug of Propofol, Using Target-Controlled Infusion in Volunteers: Retracted

GPI 15715 is the first water-soluble propofol prodrug that has been studied in humans. Present propofol lipid formulations have well known undesirable properties, for example, pain on injection and increased triglyceride concentrations. We investigated whether GPI 15715 is suitable to achieve and maintain moderate sedation for 2 h. Six male and six female volunteers received a target-controlled infusion of GPI 15715, with an initial propofol target concentration of 1.8 microg/mL and the possibility to adjust the propofol target once after 1 h. Propofol concentrations, the bispectral index, and modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) scores were monitored. The median MOAA/S score was 4 during the first hour and was 3 during the second hour of infusion. The propofol target had to be changed to 2.4 microg/mL in seven volunteers and to 3.0 microg/mL in two volunteers. A propofol concentration of 1.9 microg/mL had the highest probability to result in an MOAA/S score of 3, which corresponds with moderate sedation. We observed no serious side effects. We conclude that GPI 15715 produces excellent sedation.

Population pharmacokinetic model of sedative doses of GPI15715 and propofol liberated from GPI15715

Background GPI15715 (AQUAVAN® Injection, AQ) is a water soluble prodrug of propofol (PR). Pharmacokinetics (PK) of PR liberated from AQ differ from those of PR lipid emulsions. We developed a population PK model of AQ and liberated PR and identified covariates that influenced their PK. Methods In a Phase II colonoscopy sedation study, 5 minutes after fentanyl citrate iv dose (11–201 μg) patients received an AQ iv bolus and up to 4 supplemental iv doses (total dose 495–1675 mg). A total of 597 AQ and 599 PR concentrations from 69 males and 89 females were analyzed using NONMEM. Covariates included age (20–85 yrs, 18 patients≥ 65 yrs), weight (WT 45–140 kg), lean body weight (LBW 37–81 kg), BMI, gender, fentanyl citrate exposure, albumin, creatinine clearance, and lab values. Results Linear 2-comparment models for AQ and PR with a delay compartment between them described the data. CLAQ, V1AQ and CLPR, V1PR increased proportionally with LBW. Model parameters (%SE) under assumption of 100% AQ metabolism to PR were: CLAQ=0.27 L/min (21%), V1AQ=6.4 L (6%), K12AQ=0.023 1/min (56%), K21AQ=0.0032 1/min (52%), KAQ-PR=0.41 1/min (12%), V1PR=1 L (fixed), CLPR=3.7 L/min (18%), K12PR=3.8 1/min (25%), K21PR=0.03 1/min (27%), CLAQLBW=2.5 %/kg (12%), V1AQLBW=1.8 %/kg (21%), CLPRLBW=V1PRLBW=1.6 %/kg (27%). Conclusions Linear population PK model adequately described the data. LBW was a better predictor than WT. Fentanyl citrate did not affect the PK. No clinically significant influence of age was detected. Clinical Pharmacology & Therapeutics (2005) 77, P48–P48; doi: 10.1016/j.clpt.2004.12.076

Pharmacodynamics of AQUAVANTM Injection, a Water-Soluble Prodrug of Propofol as a Bolus Injection : A Phase I Dose Escalation Comparison with DIPRIVAN©

Pharmacodynamics of AQUAVANTM Injection, a Water-Soluble Prodrug of Propofol as a Bolus Injection : A Phase I Dose Escalation Comparison with DIPRIVAN©

Target Controlled Infusion (TCI) of AQUAVANTM, a Watersoluble Prodrug of Propofol, for Conscious Sedation in Volunteers

Target Controlled Infusion (TCI) of AQUAVANTM, a Watersoluble Prodrug of Propofol, for Conscious Sedation in Volunteers

Propofol Hemisuccinate Protects Neuronal Cells from Oxidative Injury

Oxidative stress contributes to the neuronal death observed in neurodegenerative disorders and neurotrauma. Some antioxidants for CNS injuries, however, have yet to show mitigating effects in clinical trials, possibly due to the impermeability of antioxidants across the blood-brain barrier (BBB). Propofol (2,6-diisopropylphenol), the active ingredient of a commonly used anesthetic, acts as an antioxidant, but it is insoluble in water. Therefore, we synthesized its water-soluble prodrug, propofol hemisuccinate sodium salt (PHS), and tested for its protective efficacy in neuronal death caused by non-receptor-mediated, oxidative glutamate toxicity. Glutamate induces apoptotic death in rat cortical neurons and the mouse hippocampal cell line HT-22 by blocking cystine uptake and causing the depletion of intracellular glutathione, resulting in the accumulation of reactive oxygen species (ROS). PHS has minimal toxicity and protects both cortical neurons and HT-22 cells from glutamate. The mechanism of protection is attributable to the antioxidative property of PHS because PHS decreases the ROS accumulation caused by glutamate. Furthermore, PHS protects HT-22 cells from oxidative injury induced by homocysteic acid, buthionine sulfoximine, and hydrogen peroxide. For comparison, we also tested alpha-tocopherol succinate (TS) and methylprednisolone succinate (MPS) in the glutamate assay. Although TS is protective against glutamate at lower concentrations than PHS, TS is toxic to HT-22 cells. In contrast, MPS is nontoxic but also nonprotective against glutamate. Taken together, PHS, a water-soluble prodrug of propofol, is a candidate drug to treat CNS injuries owing to its antioxidative properties, low toxicity, and permeability across the BBB.