Effect-site modelling of propofol using auditory evoked potentials
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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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Elimination rate constant
Arterial blood
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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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Objective To evaluate the pharmacokinetics,pharmacodynamics and bioequivalence of propofol medium and long chain fat emulsion injection in Chinese healthy volunteers.Methods Thirty-six Chinese healthy male volunteers were involved in the randomized cross-over study.Each subject received a single dose of 2 mg·kg-1 propofol or reference formulation.The plasma concentrations of propofol were determined by HPLC.Bispectrial index(BIS) was the main endpoint.Results The propofol belonged to three-compartment open model in vivo.After a single dose of propofol or reference formulation,the pharmacokinetics parameters of propofol were as follows:tmax were(0.05±0.02),(0.06±0.02) h;cmax were(3.59±2.36),(2.57±1.42) mg·L-1;MRT0-∞ were(1.21±0.39),(1.34±0.55) h;AUC0-∞ were(0.70±0.18),(0.64±0.17) mg·h·L-1 for propofol and reference formulation,respectively.The plasma concentration of profotol increased,and the BIS decreased with tmin-BIS were(3.31±0.71),(3.39±0.64) min,respectively.The relative bioavailability of propofol to reference formulation was F=(114.63±41.08) %.The 90%CI of cmax,AUClast,AUC0-∞ were 113.2%-156.6%,106.1%-119.2% and 100.7%-117.5%. Conclusion The two formulations were bioequivalent.
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Pain on injection is the most commonly reported adverse event after propofol injection.In a randomized, cross-over study in two groups of 12 healthy male volunteers (24-42 yr), we compared the pharmacokinetics and pharmacodynamics of two new propofol formulations (1% and 2% concentrations) in a fat emulsion consisting of medium- and long-chain triglycerides with the standard propofol formulation. After a single intravenous bolus injection of 2 mg/kg, propofol blood levels were measured for 24 h and evaluated according to an open three-compartment model. The derived pharmacokinetic variables were not different among formulations. Additionally, electroencephalographic recordings of the onset and duration of hypnotic action were comparable with all formulations. After propofol 1% in the new formulation, fewer volunteers reported severe or moderate pain on injection (9%) than after the standard formulation (59%) (P < 0.05). We attribute this result to a lower concentration of free propofol in the aqueous phase of the new formulation. Implications: Changing the composition of the carrier fat emulsion for propofol does not have an impact on the pharmacokinetics and efficacy of propofol, but it promises to provide better patient acceptance by lowering the incidence of moderate and severe pain on injection. (Anesth Analg 1997;85:1399-403)
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Fat emulsion
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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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Abstract Propofol, a highly lipophilic anaesthetic, is commercially formulated as a lipid emulsion (diprivan) for intravenous use. This formulation is characterized by rapid onset and offset of effect after rapid intravenous administration and an effect-site equilibration half-life (t 1/2 kE0) of 1.7min in rats. Paradoxically these characteristics are usually associated with relatively water-soluble anaesthetics. To test the influence of the formulation on propofol pharmacokinetics, effect-site equilibration kinetics and pharmacodynamics we performed a pharmacokinetic-pharmacodynamic study of propofol in chronically instrumented rats after administration in a lipid-free formulation. In this report we present the results of this study and compare these results with previous data obtained with rats receiving propofol in the emulsion formulation. Compared with the emulsion formulation the distribution volumes (Vdc and Vdss) were significantly higher but the t 1/2 kE0 (2.0 min) was similar for the lipid-free formulation. The concentration-effect relationship was biphasic. Propofol effect-site concentrations required to achieve 50% activation, peak activation, 50% inhibition of peak activation effect and maximum inhibition were significantly lower, indicating a higher apparent steady-state potency for the lipid-free formulation compared with the emulsion formulation. The evanescent characteristics of propofol’s effect-time-course disappeared when the anaesthetic was administered in the lipid-free formulation. These results suggest that the nature of the formulation can profoundly influence the clinical characteristics of intravenously administered drugs by modifying the pharmacokinetics or pharmacodynamics or both.
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Lipid emulsion
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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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Pain on injection is the most commonly reported adverse event after propofol injection. In a randomized, cross-over study in two groups of 12 healthy male volunteers (24-42 yr), we compared the pharmacokinetics and pharmacodynamics of two new propofol formulations (1% and 2% concentrations) in a fat emulsion consisting of medium- and long-chain triglycerides with the standard propofol formulation. After a single intravenous bolus injection of 2 mg/kg, propofol blood levels were measured for 24 h and evaluated according to an open three-compartment model. The derived pharmacokinetic variables were not different among formulations. Additionally, electroencephalographic recordings of the onset and duration of hypnotic action were comparable with all formulations. After propofol 1% in the new formulation, fewer volunteers reported severe or moderate pain on injection (9%) than after the standard formulation (59%) (P < 0.05). We attribute this result to a lower concentration of free propofol in the aqueous phase of the new formulation.Changing the composition of the carrier fat emulsion for propofol does not have an impact on the pharmacokinetics and efficacy of propofol, but it promises to provide better patient acceptance by lowering the incidence of moderate and severe pain on injection.
Pharmacodynamics
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