title: A two-compartment effect site model describes the bispectral index after different rates of propofol infusion.
abstract: 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.
authors.affiliation: Clinical Pharmacology and DMPK, AstraZeneca R&D Södertälje, 151 85, Södertälje, Sweden. marcus.bjornsson@astrazeneca.com
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Björnsson
authors.forename: Ake
authors.initials: A
authors.lastname: Norberg
authors.forename: Sigridur
authors.initials: S
authors.lastname: Kalman
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
authors.forename: Ulrika S H
authors.initials: US
authors.lastname: Simonsson
mesh_terms: D000328:Adult; D018686:Anesthetics, Intravenous / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous / Q000379:methods; D008875:Middle Aged; D008954:Models, Biological; D015742:Propofol / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D018686:Anesthetics, Intravenous; D015742:Propofol