Development and evaluation of a maturation-based predictive pharmacokinetic/pharmacodynamic model for fentanyl to help in the design of clinical studies in the paediatric population

Resumen

A maturation-based predictive pharmacokinetic/pharmacodynamic (PK/PD) model for fentanyl in paediatric care was built, by integrating key pharmacokinetic variables and principles (protein binding, clearance, distribution) as related to fentanyl PK/PD behaviour in adults (three-compartment model) and to physiological developmental changes across the paediatric population (organ weights and blood flows, body composition, renal and hepatic function, etc.). Then, extension to a PK/PD link model for fentanyl was made; under the assumption that the endogenous opioid receptor system is completely functional at birth, fentanyl PD were considered to be similar to those in adults at all paediatric ages, except for the biophase equilibrium rate constant, which was also scaled on an ontogenic basis. The proposed model was satisfactorily evaluated by comparison of the calculated parameters across the paediatric population against literature data, as well as by contrasting the simulated plasma profiles versus those obtained through a complementary and/or confirmatory alternative methodology, i.e. a physiologically based pharmacokinetic (PBPK) model developed for fentanyl in paediatrics. Moreover, juvenile animal testing in newborn piglets, considered to be a suitable experimental model for human neonates (the most unpredictable and vulnerable paediatric group), was conducted with the aim of further evaluating the predictive PK model while exploring the pharmacological responses to the drug at sedative doses. Following preliminary positive evaluation, the a-priori knowledge on fentanyl disposition generated through the developed predictive model was applied to help in the design of a non-interventional prospective study involving critical care paediatric patients treated with fentanyl for analgesia/sedation.