Abstract PR437: Calculating the Keo for the Covariates Model for Target Controlled Infusion of Propofol

Background & Objectives: The Marsh compartmental pharmacokinetic (PK) model for target controlled infusion (TCI) of propofol has previously been updated by White and colleagues by adjusting compartmental volumes and rate constants to account for gender and age[1]. To date there has been no description of the pharmacodynamic (PD) behaviour associated with this ‘Covariates Model’. The most established technique to link a PK model with PD behaviour is through creation of a theoretical ‘effect site’ compartment[2]. Calculation of the rate constant for elimination from this compartment (the ke0) allows estimation of the time course of clinical effect of a drug relative to the plasma concentration. We conducted a study to determine the appropriate ke0 to use with the Covariates Model. Materials & Methods: The study received approval from the West of Scotland Research Ethics Committee. Informed consent was gained from patients attending for elective non-cardiac surgery requiring general anaesthesia. TCI propofol was delivered using an Injectomat TIVA Agilia syringe pump (Fresenius Kabi) and the PD effect was monitored using the Bispectral Index (BIS, Medtronic). To fit the ke0 for the study population the R package nlmeODE was used to perform non-linear mixed effect modelling using differential equations[3]. Results: Thirty-three patients undergoing TCI of propofol were studied. Twenty-four of these patients were anaesthetised according to the Covariates Model as implemented by the Injectomat pump and for the other nine, plasma concentrations predicted by the Covariates Model were simulated. There were 23 females and 10 males with median age 46 years (range 28 to 75) and median weight 71 kg (range 49 to 120). Individual (random) ke0 estimates were made along with an overall population (fixed) estimate. An example comparison of these estimates is shown in figure 1. The population estimate for ke0 fitted for the Covariates Model was 0.254 min-1.Conclusion: From this study, an appropriate ke0 to use with the Covariates Model is 0.254 min-1. This is similar to the original ke0 used in the Marsh Model as implemented by the Diprifusor®. References: 1. White M, Kenny GN, Schraag S Use of target controlled infusion to derive age and gender covariates for propofol clearance. Clin Pharmacokinet 2008; 47: 119-27. 2. Sheiner LB, Stanski DR, Vozeh S, Miller RD, Ham J Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. Clin Pharmacol Ther 1979; 25: 358-71. 3. Tornoe CW. nlmeODE: Non-linear mixed-effects modelling in nlme using differential equations. R package version 1.1, 2012. Disclosure of Interest: C. Hawthorne: None declared, S. Schraag Conflict with: Consultancy fees from Fresenius Kabi and lecture honorarium from Covidien Medtronic, N. Suttcliffe Conflict with: Previously received honoraria from AstraZeneca, B Braun, GE and GSK, S. McKelvie: None declared, M. Shaw: None declared, M. Chandran: None declared