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A two-compartment effect site model describes the bispectral index after different rates of propofol infusion
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
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2010 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 37, no 3, 243-255 p.Article in journal (Refereed) Published
Abstract [en]

Different estimates of the rate constant for the effect site distribution (k(e0)) of propofol, depending on the rate and duration of administration, have been reported. This analysis aimed at finding a more general pharmacodynamic model that could be used when the rate of administration is changed during the treatment. In a cross-over study, 21 healthy volunteers were randomised to receive a 1 min infusion of 2 mg/kg of propofol at one occasion, and a 1 min infusion of 2 mg/kg of propofol immediately followed by a 29 min infusion of 12 mg kg(-1) h(-1) of propofol at another occasion. Arterial plasma concentrations of propofol were collected up to 4 h after dosing, and BIS was collected before start of infusion and until the subjects were fully awake. The population pharmacokinetic-pharmacodynamic analysis was performed using NONMEM VI. A four-compartment PK model with time-dependent elimination and distribution described the arterial propofol concentrations, and was used as input to the pharmacodynamic model. A standard effect compartment model could not accurately describe the delay in the effects of propofol for both regimens, whereas a two-compartment effect site model significantly improved the predictions. The two-compartment effect site model included a central and a peripheral effect site compartment, possibly representing a distribution within the brain, where the decrease in BIS was linked to the central effect site compartment concentrations through a sigmoidal E-max model.

Place, publisher, year, edition, pages
2010. Vol. 37, no 3, 243-255 p.
Keyword [en]
Propofol, Pharmacokinetics, Pharmacodynamics, Bispectral index, NONMEM
National Category
Pharmaceutical Sciences Medical and Health Sciences
URN: urn:nbn:se:uu:diva-136145DOI: 10.1007/s10928-010-9157-1ISI: 000279034400002OAI: oai:DiVA.org:uu-136145DiVA: diva2:376473
Available from: 2010-12-10 Created: 2010-12-10 Last updated: 2014-01-22Bibliographically approved
In thesis
1. Pharmacometric Models in Anesthesia and Analgesia
Open this publication in new window or tab >>Pharmacometric Models in Anesthesia and Analgesia
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Modeling is a valuable tool in drug development, to support decision making, improving study design, and aid in regulatory approval and labeling. This thesis describes the development of pharmacometric models for drugs used in anesthesia and analgesia.

Models describing the effects on anesthetic depth, measured by the bispectral index (BIS), for a commonly used anesthetic, propofol, and for a novel anesthetic, AZD3043, were developed. The propofol model consisted of two effect-site compartments, and could describe the effects of propofol when the rate of infusion is changed during treatment. AZD3043 had a high clearance and a low volume of distribution, leading to a short half-life. The distribution to the effect site was fast, and together with the short plasma half-life leading to a fast onset and offset of effects. It was also shown that BIS after AZD3043 treatment is related to the probability of unconsciousness similar to propofol.

In analgesia studies dropout due to lack of efficacy is common. This dropout is not at random and needs to be taken into consideration in order to avoid bias. A model was developed describing the PK, pain intensity and dropout hazard for placebo, naproxen and a novel analgesic compound, naproxcinod, after removal of a wisdom tooth. The model provides an opportunity to describe the effects of other doses or formulations. Visual predictive checks created by simultaneous simulations of PI and dropout provided a good way of assessing the goodness of fit when there is informative dropout.

The performance of non-linear mixed effects models in the presence of informative dropout, with and without including models that describe such informative dropout was investigated by simulations and re-estimations. When a dropout model was not included there was in general more bias. The bias increased with decreasing number of observations per subject, increasing placebo effect and increasing dropout rate. Bias was relatively unaffected by the number of subjects in the study. The bias had, in general, little effect on simulations of the underlying efficacy score, but a dropout model would still be needed in order to make realistic simulations.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 56 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 173
Pharmacometrics, Anesthesia, Analgesia, Dropout, NONMEM
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
urn:nbn:se:uu:diva-205580 (URN)978-91-554-8726-3 (ISBN)
Public defence
2013-10-04, B22, Uppsala Biomedicinska Centrum (BMC), Husargatan 3, Uppsala, 13:15 (English)
Available from: 2013-09-13 Created: 2013-08-20 Last updated: 2014-01-22

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Karlsson, Mats O.Simonsson, Ulrika S. H.
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