Systematic evaluation of propofol population pharmacokinetic models and development of a literature-supported new meta-model for critically ill preterm and term neonates

Propofol pharmacokinetics in neonates is characterised by pronounced developmental variability, and performance of existing models in preterm neonates remains insufficiently characterized. We systematically evaluated published propofol population pharmacokinetic models suitable for neonates and developed a new literature-supported meta-model. A new dataset was obtained using opportunistic volumetric absorptive microsampling from preterm and term neonates. Neonates (n = 40, median gestational age: 32.7 weeks) receiving 2 mg/kg propofol for procedural sedation were studied. Blood samples (10 µl) were collected to Mitra™ microsampling devices during 24 h after propofol dose coinciding with routine clinical blood sampling. Propofol concentrations were quantitated with HPLC-MS/MS method. Three published propofol population pharmacokinetic models were compared using numerical and graphical tests of goodness-of-fit and predictive performance. Population modelling was conducted using NONMEM® and the $PRIOR subroutine to describe the time-course of whole-blood concentrations of propofol. No published model adequately described propofol concentration-time course in our new dataset. A sensitivity analysis of clearance maturation structures showed that replacing the base model with alternative formulations of postnatal adaptation (discrete step), postmenstrual age-based sigmoidal maturation, or higher allometric exponents for clearance (1.11 and 1.20 instead of 0.75) decreased the predictive performance of the model. A population pharmacokinetic meta-model incorporating prior information from published neonatal models was developed. Clearance maturation was parameterised as the product of a gestational component and an early postnatal adaptation component. All clearance and distribution parameters were scaled with allometric weight scaling. The final model estimated propofol concentration-time course with reasonable precision and predictive performance in preterm infants.