Browsing by Subject "nonlinear mixed effects model"

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  • Bäckström, Mia (Helsingfors universitet, 2017)
    Background: Dexmedetomdine is a α2-adrenergic receptor agonist, which by binding to the α2-adrenergic receptor in the sympathetic nervous system exhibits sedative effect. Additionally, it has an analgesic and anxiolytic effect. Dexmedetomidine is registered as a sedative for use in the intensive care unit and in USA, additionally, in surgical settings. The study was conducted to characterize the pharmacokinetics in healthy volunteers through pharmacokinetic analysis methods. Methods: The clinical study was conducted on healthy 10 voluntary subjects each receiving dose of 1 µg/kg both intravenously (IV) and subcutaneously (SC). The study session lasted for 10 hours, with a wash-out period of at least 7 days between consecutive administrations. Arterial blood samples were taken to determine the plasma concentrations of dexmedetomidine. The pharmacokinetics of the IV and SC dose were determined by noncompartmental analysis (NCA) and, additionally, population modeling using nonlinear mixed effects model (NONMEM) was used to determine the pharmacokinetics of the IV dose. Results: The population's mean clearance after the IV dose was 40.0 L/h and for SC 45.6 L/h. The elimination half-life was 2 hours for IV, whereas terminal half-life was 9 hours for the SC dose. The SC bioavailability was 120 %. From the population modeling the typical elimination clearance, volume of distribution in central compartment, inter-compartmental clearance, and volume of distribution in the second compartment were 39.6 L/h, 13.7 L, 116 L/h, and 77 L, respectively. Conclussion: The obtained pharmacokinetic parameter values from NCA for IV were in line with the results from previous studies. For the SC dose the pharmacokinetic parameter values had high SD indicating high inter-individual variations. However, when the 8th subject was excluded from data analysis less SD was obtained and the result resembled more the results from other extravascular studies. The pharmacokinetic population results for IV dexmedetomidine were similar to previous studies on healthy subjects. Weight was used as a covariate, and was modeled by allometrically scaling the parameters. From the results it is shown that the covariate improved the model's goodness of fit.