Pharmacokinetics and Clinical Pharmacodynamics of the New Propofol Prodrug GPI 15715 in Volunteers: Retracted
J. FechnerHarald IhmsenDirk HatterscheidChristine SchießlJames J. VornovEric BurakH. SchwildenJ. Schüttler
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Background: GPI 15715 (AQUAVAN injection) is a new watersoluble prodrug which is hydrolyzed to release propofol.The objectives of this first study in humans were to investigate the safety, tolerability, pharmacokinetics, and clinical pharmacodynamics of GPI 15715.Methods: Three groups of three healthy male volunteers (aged 19 -35 y, 67-102 kg) received 290, 580, and 1,160 mg GPI 15715 as a constant rate infusion over 10 min.The plasma concentrations of GPI 15715 and propofol were measured from arterial and venous blood samples up to 24 h.Pharmacokinetics were analyzed with compartment models.Pharmacodynamics were assessed by clinical signs.Results: GPI 15715 was well tolerated without pain on injection.Two subjects reported a transient unpleasant sensation of burning or tingling at start of infusion.Loss of consciousness was achieved in none with 290 mg and in one subject with 580 mg.After 1,160 mg, all subjects experienced loss of consciousness at propofol concentrations of 2.1 ؎ 0.6 g/ml.A two-compartment model for GPI 15715 (central volume of distribution, 0.07 l/kg; clearance, 7 ml • kg ؊1 min ؊1 ; terminal half-life, 46 min) and a three-compartment model for propofol (half-lives: 2.2, 20, 477 min) best described the data.The maximum decrease of blood pressure was 25%; the heart rate increased by approximately 35%.There were no significant laboratory abnormalities.Conclusions: Compared with propofol lipid emulsion, the potency seemed to be higher with respect to plasma concentration but was apparently less with respect to dose.Pharmacokinetic simulations showed a longer time to peak propofol concentration after a bolus dose and a longer context-sensitive half-time.Keywords:
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SummaryBackground and objective: We studied the pharmacokinetics and pharmacodynamics of GPI 15715 (Aquavan® injection), a new water-soluble prodrug metabolized to propofol by hydrolysis.Methods: 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.Results: A maximum propofol concentration of 7.1 ± 1.7 μg 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 μg mL−1, ke0 = 0.35 ± 0.04 min−1).Conclusions: 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.
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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 Fechner J, Ihmsen H, Hatterscheid D, Jeleazcov C, Schiessl C, Vornov JJ, Schwilden H, Schüttler J: Comparative pharmacokinetics and pharmacodynamics of the new propofol prodrug GPI 15715 and propofol emulsion. Anesthesiology 2004; 101:626–39
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European Journal of Anaesthesiology: April 2010 - Volume 27 - Issue 4 - p 402 doi: 10.1097/EJA.0b013e3283389f5c
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The pharmacokinetics of propofol were determined in nine patients (seven men, two women, (mean +/- SD) 55.8 +/- 21.2 yr, 65.2 +/- 8 kg) requiring prolonged mechanical ventilation of their lungs. After an initial dose of 1-3 mg/kg, propofol was administered iv at 3 mg/kg/h for 72 h. Arterial blood samples were collected at selected times during and up to 72 h after infusion. Propofol whole blood concentrations were determined by high-performance liquid chromatography with fluorescence detection. Individual pharmacokinetic parameters were estimated by noncompartmental analysis. Derived pharmacokinetic parameters showed a long terminal phase (T1/2 = 1878 +/- 672 min), a large volume of distribution at steady state (Vdss = 1666 +/- 756 l), and a high total body clearance (Cl = 1.57 +/- 0.56 l/min). While the propofol terminal elimination half-life is longer than that previously reported, emergence from sedation after prolonged administration will be governed by both redistribution mechanisms arising from the large distribution volumes and elimination from the body.
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Introduction: Niclosamide (Nc) is an FDA-approved anthelmintic drug that was recently identified in a drug repurposing screening to possess antiviral activity against SARS-CoV-2. However, due to the low solubility and permeability of Nc, its in vivo efficacy was limited by its poor oral absorption. Method: The current study evaluated a novel prodrug of Nc (PDN; NCATS-SM4705) in improving in vivo exposure of Nc and predicted pharmacokinetic profiles of PDN and Nc across different species. ADME properties of the prodrug were determined in humans, hamsters, and mice, while the pharmacokinetics (PK) of PDN were obtained in mice and hamsters. Concentrations of PDN and Nc in plasma and tissue homogenates were measured by UPLC-MS/MS. A physiologically based pharmacokinetic (PBPK) model was developed based on physicochemical properties, pharmacokinetic and tissue distribution data in mice, validated by the PK profiles in hamsters and applied to predict pharmacokinetic profiles in humans. Results: Following intravenous and oral administration of PDN in mice, the total plasma clearance (CLp) and volume of distribution at steady-state (Vdss) were 0.061-0.063 L/h and 0.28-0.31 L, respectively. PDN was converted to Nc in both liver and blood, improving the systemic exposure of Nc in mice and hamsters after oral administration. The PBPK model developed for PDN and in vivo formed Nc could adequately simulate plasma and tissue concentration-time profiles in mice and plasma profiles in hamsters. The predicted human CLp/F and Vdss/F after an oral dose were 2.1 L/h/kg and 15 L/kg for the prodrug respectively. The predicted Nc concentrations in human plasma and lung suggest that a TID dose of 300 mg PDN would provide Nc lung concentrations at 8- to 60-fold higher than in vitro IC50 against SARS-CoV-2 reported in cell assays. Conclusion: In conclusion, the novel prodrug PDN can be efficiently converted to Nc in vivo and improves the systemic exposure of Nc in mice after oral administration. The developed PBPK model adequately depicts the mouse and hamster pharmacokinetic and tissue distribution profiles and highlights its potential application in the prediction of human pharmacokinetic profiles.
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Background: GPI 15715 (AQUAVAN injection) is a new watersoluble prodrug which is hydrolyzed to release propofol.The objectives of this first study in humans were to investigate the safety, tolerability, pharmacokinetics, and clinical pharmacodynamics of GPI 15715.Methods: Three groups of three healthy male volunteers (aged 19 -35 y, 67-102 kg) received 290, 580, and 1,160 mg GPI 15715 as a constant rate infusion over 10 min.The plasma concentrations of GPI 15715 and propofol were measured from arterial and venous blood samples up to 24 h.Pharmacokinetics were analyzed with compartment models.Pharmacodynamics were assessed by clinical signs.Results: GPI 15715 was well tolerated without pain on injection.Two subjects reported a transient unpleasant sensation of burning or tingling at start of infusion.Loss of consciousness was achieved in none with 290 mg and in one subject with 580 mg.After 1,160 mg, all subjects experienced loss of consciousness at propofol concentrations of 2.1 ؎ 0.6 g/ml.A two-compartment model for GPI 15715 (central volume of distribution, 0.07 l/kg; clearance, 7 ml • kg ؊1 min ؊1 ; terminal half-life, 46 min) and a three-compartment model for propofol (half-lives: 2.2, 20, 477 min) best described the data.The maximum decrease of blood pressure was 25%; the heart rate increased by approximately 35%.There were no significant laboratory abnormalities.Conclusions: Compared with propofol lipid emulsion, the potency seemed to be higher with respect to plasma concentration but was apparently less with respect to dose.Pharmacokinetic simulations showed a longer time to peak propofol concentration after a bolus dose and a longer context-sensitive half-time.
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GPI 15715 is a new water-soluble prodrug that is hydrolyzed to release propofol. The objectives of this crossover study in volunteers were to investigate the pharmacokinetics and pharmacodynamics of GPI 15715 in comparison with propofol emulsion.In two separate sessions, nine healthy male volunteers (19-35 yr, 70-86 kg) received GPI 15715 and propofol emulsion as a target controlled infusion over 60 min. In the first 20 min, the propofol target concentration increased linearly to 5 microg/ml. Subsequently, the targets were reduced to 3 microg/ml and 1.5 microg/ml for 20 min each. The plasma concentrations of GPI 15715 and propofol were measured from arterial and venous blood samples up to 24 h and pharmacokinetics were analyzed. The pharmacodynamic effect was measured by the median frequency of the power spectrum of the electroencephalogram, and a sigmoid model with effect compartment was fitted to the data.Compared with propofol emulsion, propofol from GPI 15715 showed a different disposition function and especially larger volumes of distribution. The propofol effect site concentration for half maximum effect was 2.0 +/- 0.5 microg/ml for GPI 15715 and 3.0 +/- 0.7 microg/ml for propofol emulsion (P < 0.05). Propofol from GPI 15715 did not show a hysteresis between plasma concentration and effect.Compared with propofol emulsion, propofol from GPI 15715 showed different pharmacokinetics and pharmacodynamics, particularly a higher potency with respect to concentration. These differences may indicate an influence of the formulation.
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Target-controlled infusion (TCI) of propofol is used for general anesthesia. However, the only pharmacokinetic parameter commercially used for Japanese patients is weight, and pharmacokinetic models are based on European physical attributes. Drug metabolism also differs in races. This study aimed to identify optimal continuous doses of propofol for Japanese patients and to create a simulated pharmacokinetic (PK) model. Thirty Japanese patients were enrolled. Patients received a constant infusion of 9 mg/kg/h of propofol. Arterial blood samples were collected and the time course of plasma propofol concentrations was modeled using the nonlinear mixed effects model (NONMEM) three-compartmental PK model. We validated the model by intravenously injecting 10 patients with a TCI driver system programmed with the NONMEM model. Our model’s performance was evaluated using the median prediction error (MDPE), median absolute prediction error (MDAPE), and Wobble. We analyzed 320 blood samples for model building and 160 samples for validating our new model. The calculated parameters for the three-compartmental PK model were volume [V1, 3.58; V2, 13.0 + 0.49 × (Age—64); and V3, 186] and elimination clearance [CL1, 0.77 + (WT—54) × 0.04 + (HT—158) × 0.03; CL2, 0.89 + 0.12 × (Age—64); and CL3, 0.98 × exp ((Age—64)/10)]. The new model improved MDPE, MDAPE, and Wobble values (11.5% ± 43.8%, 14.3% ± 33.0%, and 25.0% ± 21.3%, respectively). We created a new pharmacokinetic model for Japanese patients, which is more accurate than the three existing models applied to Japanese populations. Electronic document is a “live” template. The various components of your paper [title, text, heads, etc.] are already defined on the style sheet, as illustrated by the portions given in this document.
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Objective To investigate the pharmacokinetics of propofol in children of different ages after a single dose. Methods Thirty-five ASA Ⅰ or Ⅱ children were divided into 3 age groups: group A 3 yr; group B ≥ 3- 5 yr and group C≥5- 10 yr. Arterial blood samples of 1 ml were obtained at 2, 4, 6, 8, 10, 20, 30, 45, 60, 90, 120, 180 min after a bolus dose of propofol (3 mg·kg-1) . The plasma concentrations (Cp) of propofol were measured by using high performance liquid chromatograph with ultraviolet detector. The data obtained were analyzed by 3P87 pharmacokinetic software. Results The Cp of propofol decreased rapidly after intravenous bolus injection in all 3 groups. The curve for Cp vs time was fitted to a three-compartment pharmacokinetic model. Group A had a significantly smaller mean exponent γ(P0.01) leading to a significantly longer mean elimination half-life gamma (T1/2 γ) compared with group C. There were no significant differences in central volume of distribution (Vc) , total clearance (CL), apparent volume of distribution (Vd) and other parameters including rate constants K12, K21 , K10 among the 3 groups. Conclusion The Cp versus time curve for propofol is best described by a three-compartment pharmacokinetic model. Elimination of propofol is prolonged in children less than 3 yr of age.
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