Modelagem farmacocinética baseada em Fisiologia para prever perfis plasmáticos de propofol em cães saudáveis e com diferentes graus de disfunção hepática

Abstract

A physiologically based pharmacokinetic (PBPK) model allows the prediction of the concentration or amount of a drug in different tissues and organs over time. It can be used to simulate and optimize different therapeutic protocols in both healthy and diseased individuals. The objective of this study was to develop a PBPK model for propofol plasma profiles in healthy dogs and dogs with hepatic dysfunction.The study methodology was divided into two phases. The first phase involved creating the PBPK model for healthy dogs, while in the second phase, this model was adjusted for dogs with hepatic insufficiency. The model was developed based on pharmacokinetic studies available in the literature and the physicochemical properties of the drug, obtained from the DrugBank database. Model construction was performed using PK-Sim software, while validation was conducted in RStudio, where the geometric mean fold error (GMFE) was calculated as an evaluation metric. The model for healthy dogs showed good predictive performance, as evidenced by the GMFE performance measure, which ranged from 0.8 to 1.25, meeting the twofold error criterion. The simulated regimen for healthy dogs—5mg/kg (administered as a bolus) followed by a continuous infusion at a rate of 0.13 mg/kg/min—was sufficient and ensured that all simulated individuals reached the target plasma concentration. For dogs with 60% and 40% hepatic function, infusion rate adjustments were made to ensure that individuals did not exceed the therapeutic window necessary for anesthesia maintenance. The results presented indicate the efficacy and practicality of a PBPK model for propofol in dogs, with a special focus on hepatic insufficiency.