A pharmacokinetic model optimized by covariates for propofol target-controlled infusion in dogs

To develop a population pharmacokinetic model for propofol target-controlled infusion (TCI) in dogs and to evaluate its performance for use in the clinical setting.

Prospective clinical study.

A group of 40 client-owned dogs undergoing general anaesthesia for magnetic resonance imaging.

Propofol was administered to 26 premedicated dogs and arterial blood samples were collected during the infusion and over 240 minutes after terminating the infusion. Propofol concentrations were measured by high-performance liquid chromatography. A population pharmacokinetic analysis was performed using a nonlinear mixed-effects modelling approach, allowing inter- and intra-individual variability estimation and quantitative evaluation of the influence of the following covariates: weight, body condition score, age, size-related age (Age_size), sex, premedication type, size and contrast agent administration. A final model was obtained using a stepwise approach in which individual covariate effects on each pharmacokinetic variable were incorporated. The performance of the developed TCI model was subsequently evaluated while inducing and maintaining anaesthesia in 14 premedicated dogs and assessed by comparing predicted and measured concentrations at specific time points.

Propofol pharmacokinetics was best described by a three-compartment model. Weight, Age_size, premedication and sex showed significant pharmacokinetic effects. Addition of the significant covariate/variable associations to the final model resulted in a reduction of the objective function value from 285.53 to -22.34. The median values of prediction error and absolute performance error were 3.1% and 28.4%, respectively. Induction targets between 4.0 and 6.5 μg mL^-1 allowed intubation within 5.0 ± 0.9 minutes. Anaesthesia was achieved with targets between 3.0 and 6.5 μg mL^-1. Mean time to extubation was 9.7 ± 2.6 minutes. All dogs recovered smoothly and without complications.

Overall predictive performance of the pharmacokinetic model-driven infusion developed was clinically acceptable for administering propofol to dogs in routine anaesthesia.