A two-compartment effect site model describes the Bispectral Index Score (BIS) after administration of propofol
Marcus A. Björnsson (1,3), Åke Norberg (2), Sigridur Kalman (2), Mats O. Karlsson (3), Ulrika S.H. Simonsson (3)
(1) Clinical Pharmacology and DMPK, AstraZeneca R&D Södertälje, Sweden; (2) Karolinska Institute at Department of Anesthesiology and Intensive Care, Karolinska University Hospital, Huddinge, Sweden; (3) Department of Biopharmaceutical Sciences, Uppsala University, Sweden
Objectives: Different estimates of the rate constant for the effect-site distribution (ke0) of propofol have been reported, depending on the rate and duration of administration [1,2]. This analysis aimed at finding a more general pharmacodynamic model that could be used when the rate of administration is changed during the treatment.
Methods: Twenty healthy volunteers were randomized to receive a 1-minute infusion of 2 mg/kg of propofol at one occasion, and a 1-minute infusion of 2 mg/kg of propofol (bolus) immediately followed by a 29-minute infusion of 12 mg/kg/hour of propofol (primed constant infusion) at another occasion, in a cross-over fashion. Arterial plasma concentrations of propofol were collected up to 4 hours after dosing, and Bispectral Index Score (BIS) was collected before start of infusion and until the subjects were regarded as no longer sedated after the anaesthesia. The population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed using NONMEM VI. Goodness of fit was assessed using objective function values, standard errors, graphics and visual predictive checks.
Results: A three-compartment model under-estimated the propofol concentrations during the constant infusion. An empirical model with time-dependent clearance parameters described the PK better for both regimens, and was used as an input to the PD model. An effect-compartment model could not accurately describe the delay in the effects of propofol for both treatments. When a two-compartment effect site model was used to describe the PD the predictions were significantly improved. The model included a central and a peripheral effect site compartment. The decrease in BIS was linked to the central effect site compartment concentrations through a sigmoidal Emax model. The rate constants from plasma compartment to effect site, and from central to peripheral effect site and back were approximately 0.2, 0.1 and 0.02 min-1, respectively. Inter-individual variability in PD parameters was moderate.
Conclusions: The time-courses of BIS after both treatments were well described by a two-compartment effect-site model, possibly representing a distribution within the brain.
References:
[1] Doufas A.G. et al., Anesthesiology 2004; 101:1112-21
[2] Struys M.M.R.F. et al., Anesthesiology 2007; 107:386-96
