Modelling the Maturation of Fentanyl Pharmacokinetics in Children

Abstract

Aims: Fentanyl is a potent opioid analgesic used within the hospital setting for the management of acute pain within children following surgical procedures. The dosing of fentanyl in the paediatric population should be approached differently from new-borns up to children. The best approach for dosing fentanyl in this population remains unclear and required investigation. The aim of this thesis was to model the maturation of fentanyl pharmacokinetics, through simulated paediatric and adult data to assess the influence of age and size related changes. The aim was also model the changes in absorption fentanyl pharmacokinetics for nasal and Fentanyl Oralet formulations. Method: Concentration-time data from 322 patients aged premature neonate to adult was simulated based on previous studies done within literature, to create a population dataset used for the analysis of fentanyl PK. Simulated concentration-time date was modelled to assess the influence of size and age covariates on predicting the clearance and volume of distribution for fentanyl. This data was modelled by 1, 2 and 3 compartment models for comparison to select the model of best fit. Size and age-related changes in clearance and volume were investigated using theory-based allometry with sigmoidal and linear maturation functions for clearance and volume. Concentration-time data from 122 adult patients receiving nasal administration of fentanyl and 33 child patients receiving fentanyl Oralet was used to describe fentanyl absorption pharmacokinetics. Results: A 3-compartment model with a maturation function for clearance and volumes was selected as the most appropriate model for describing fentanyl pharmacokinetics from neonates to adults. Size and age covariates were shown to predict majority of the pharmacokinetic variability within fentanyl clearance and volume of distribution. Clearance was shown to increase with age and matured during the first year of infancy, reaching adult values after around 1 year post birth. Volume was shown to decrease with age, becoming elevated at birth and slowly decreasing towards adults’ values after 1 year post birth. Absorption pharmacokinetics for both nasal and Fentanyl Oralet formulations were described however with some variability when compared to literature. Conclusion: Size and age covariates can be used to reliably predict the pharmacokinetics of fentanyl from neonates up to adults. Use of a 3-compartment model best described the concentration-time data of fentanyl within this population. Further work is needed involving a pharmacodynamics-based model to describe the concentration-effect relationship of fentanyl, resulting in a link between dose and effect.