Development and optimization of a fentanyl pharmacokinetic model for target-controlled infusion in anaesthetized dogs

Objective To investigate pharmacokinetics (PK) of fentanyl administered by target-controlled infusion (TCI), and to develop a PK model optimized by covariates for TCI in anaesthetized dogs. Study design Prospective clinical study. Animals A group of 20 client-owned dogs with spinal pain undergoing anaesthesia for magnetic resonance imaging. Methods Fentanyl was administered as an infusion to 20 anaesthetized dogs using a TCI system incorporating a previously described fentanyl two-compartment PK. Arte-rial blood samples were collected at specific time points during the infusion and over 60 minutes post-infusion for measurement of fentanyl plasma concentrations. The pre-dictive performance of the Sano PK model was assessed by comparing predicted and measured plasma concentrations. A population PK analysis was then performed using a nonlinear mixed-effect modelling approach, allowing inter -and intra-individual variability estimation. Finally, a quantitative stepwise evaluation of the influence of various covariates such as weight, body condition score, size, size -related age, sex and type of premedication on the PK model was considered. Results Overall predictive performance of the Sano PK set of variables was not clinically acceptable in anaesthetized dogs. Fentanyl PK was best described by a three -compartment model. Weight and sex were found to affect the volume of distribution of the central compartment. Addition of these two covariate/variable associations resulted in a reduction of the objective function value (OFV) from -340.18 to -448.34, and of the median population weighted residual and the median population absolute weighted residual from 16.1% and 38.6% to 3.9% and 20.3%, respectively. Fentanyl infusions at measured con-centrations up to 5.4 ng mL-1 in sevoflurane-anaesthetized dogs resulted in stable anaesthesia and smooth recoveries without complications. Conclusions and clinical relevance A population three -compartment PK model for fentanyl TCI in anaesthetized dogs was developed. Weight and sex have been detected and incorporated as significant covariates.