PHARMACOKINETICS OF REMIFENTANIL: METABOLISM AND MODELING

Remifentanil is an opioid derivative, characterized by high potency and reduced cardiovascular toxicity. It is an ultra-short acting drug and it is subjected to metabolism by esterases in blood and other tissues. Purpose. The aim of this work is to study the Remifentanil pharmacokinetics using both an in vitro approach to study its metabolism and modeling its concentration evolution along the human body to individuate the key parameters which can lead to an individualized therapy. Materials and Methods. To evaluate the in vitro degradation kinetic, the Remifentanil concentration evolution in a solution (initial concentration of 20000 ng/mL) kept at 37°C and Ph 7.4 (mimicking the blood value) has been evaluated during the time. Samples of the medium have been withdrawn and analyzed by HPLC. With this method, the degradation due to the temperature effect can be evaluated. Following the same procedure, the degradation effect due to the metabolism caused by the addition of esterase has been evaluated. Finally, the Remifentanil pharmacokinetics has been modeled using a physiologically based pharmacokinetic model, in order to predict the drug concentration in the blood. Results. The in vitro results have shown that the drug is subjected to a degradation if exposed for prolonged time at physiological temperature. Moreover, the addition of esterases in the Remifentanil solution causes a further decrease in the concentration values, demonstrating a metabolic effect due to the enzymes presence in solution. The model simulations have been compared with in vivo plasma concentrations of the drug finding a good agreement between the model curves and the experimental data, both in the case of intravenous constant-rate infusion and of bolus injection. Conclusions. The metabolism of Remifentanil has been studied in vitro to understand the key factors which influence its degradation and it has been modeled to describe, and eventually predict, its pharmacokinetics.