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
Reference: PAGE 18 () Abstr 1590 [www.page-meeting.org/?abstract=1590]
Poster: Applications- CNS