A two-compartment effect site model describes the bispectral index after different rates of propofol infusion |
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Authors: | Marcus A Björnsson Åke Norberg Sigridur Kalman Mats O Karlsson Ulrika S H Simonsson |
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Institution: | 1.Clinical Pharmacology and DMPK,AstraZeneca R&D S?dert?lje,S?dert?lje,Sweden;2.Karolinska Institutet at Department of Anaesthesia and Intensive Care,Karolinska University Hospital,Huddinge,Sweden;3.Department of Pharmaceutical Biosciences,Uppsala University,Uppsala,Sweden |
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Abstract: | Different estimates of the rate constant for the effect site distribution (ke0) 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 Emax model. |
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