Pharmacokinetic/pharmacodynamic modelling to optimize the dose of analgesics and sedatives in children

Analgesic and sedative drugs are mostly used in an “off label” fashion in children. The pharmacokinetic-pharmacodymamic (PK/PD) approach is useful in order to determine the dose-concentration-response relationship and therefore the optimal dose regimens in different populations. However, this approach has not been fully explored for all analgesics and sedatives. This is mostly due to the complex and multidimentional nature of pain, making it challenging to evaluate objectively their effect particularly in neonates and infants. Hence, there is an important need for PK/PD studies in pain and sedation. This thesis focuses on analysing clinical trial results on specific areas that lack good quality PK/PD data in order to optimise the dose of analgesic and sedative agents in children. The studies described in this thesis aimed to address the following questions: what is the optimal dose of fentanyl for procedural pain in preterm infants (NEOFENT study); what is the adequate dose regimen of fentanyl and clonidine to provide an adequate pain and sedation management in asphyxiated newborns receiving hypothermic treatment (SANNI study); and finally what is the optimal dose of clonidine and midazolam in the PICU (CloSed study). In order to address these questions, PK and PK/PD models were developed in order to describe the relationship between drug concentration and analagesic/sedative effect using pain and sedation scores. These models were used to define target concentrations and perform simulations to determine the optimal dose. The results of the NEOFENT study showed that three genetic variants had a significant influence on the fentanyl clearance and suggested an IV dose of 2 µg/kg for procedural pain in preterm infants. The results of the SANNI analysis showed that the hypothermic treatment significantly decreased the clearance of both fentanyl and clondine. Finally, the models developed for the CloSed and SANNI studies suggested that the dose routinely prescribed in clinical practice should be increased in order to provide an adequate pain and sedation management