Clinical Validation of the Covariates Pharmacokinetic Model for Propofol in an Adult Population

Abstract

Background and objective: Pharmacokinetic or pharmacokinetic-pharmacodynamic models have been instrumental in facilitating the clinical use of propofol in target-controlled infusion systems in anaesthetic practice. There has been debate over which model should be recommended for practice. The covariates model is an updated pharmacokinetic model for propofol. The aim of this study was to prospectively validate this model in an adult population.

Methods: Twenty-nine patients were included, with a range of ages to assess model performance in younger and older individuals. Subjects received propofol through a target-controlled infusion device programmed with the covariates model. Subjects were randomised to one of two increasing/decreasing regimes of propofol plasma target concentrations between 2 and 5 μg.mL^-1. After the start of the infusion, arterial and venous blood samples were drawn at pre-specified timepoints between 1.5 and 20 min and between 1.5 and 45 min, respectively. Predictive performance was assessed using established methodology.

Results: The model achieved a bias of 9 (- 45 to 82) and precision of 24 (9-82) for arterial samples and bias of - 8 (- 64 to 70) and precision of 23 (9-70) for venous samples. Predicted concentrations tended to be higher than the measured concentrations in female individuals but lower in male individuals. There was no clear systematic difference in the bias between younger and older patients.

Conclusions: The covariates propofol pharmacokinetic model achieved an acceptable level of predictive performance, as assessed by both arterial and venous sampling, for use in target-controlled infusion in clinical practice.

Clinical trial registration: NCT01492712 (15 December, 2011).

Fig. 1

Study algorithm. Red box represents an arterial sample taken, blue box represents a venous sample taken. BIS bispectral index, Cp target plasma concentration, GA general anaesthesia, loC level of consciousness, TCI target-controlled infusion

Fig. 2

Validation study results showing the median performance error (MDPE) and median absolute performance error (MDAPE) for arterial and venous samples. The horizontal black dashed line signifies an MDPE of 0, while the horizontal grey dashed lines signify MDPEs of + 20 and − 20, which represents clinically acceptable performance [16]

Fig. 3

Summary of results for prediction errors based on arterial blood sampling in simulation studies for each of the covariates, Marsh et al., Schnider et al. and Eleveld et al. models in all patients (A), female patients (B) and male patients (C). The horizontal black dashed line signifies a median performance error (MDPE) of 0, while the horizontal grey dashed lines signify MDPEs of + 20 and − 20, which represents clinically acceptable performance [16]

Fig. 4

Summary of results for prediction errors based on venous blood sampling in simulation studies for each of the covariates, Marsh et al., Schnider et al. and Eleveld et al. models in all patients (A), female patients (B) and male patients (C). The horizontal black dashed line signifies a median performance error (MDPE) of 0, while the horizontal grey dashed lines signify MDPEs of + 20 and − 20, which represents clinically acceptable performance [16]

Fig. 5

Summary of results for prediction errors based on arterial (A) and venous (B) blood sampling in simulation studies for each of the covariates (“C”), Marsh et al. (“M”), Schnider et al. (“S) and Eleveld et al. (“E”) models at set timepoints following an increase in target plasma concentrations. The horizontal black dashed line signifies a median performance error of 0, while the horizontal grey dashed lines signify MDPEs of + 20 and − 20, which represents clinically acceptable performance [16]. mins minutes