■ DISCUSSION
This study presents a population pharmacokinetic model for propofol in (pre)term neonates and infants, based on a large pooled dataset in this specific population. Traditionally, propofol elimination clearance maturation is accounted for using size (e.g . BW) and/or age (e.g. PMA) covariates only8,11. Accounting for GA and PNA (as continuous covariates) instead of aggregation of these metrics into postmenstrual age (PMA) improves the description of the pharmacokinetics of propofol in a population including both (pre)term neonates and infants. In the final model, we demonstrate the necessity to account separately for GA and PNA to optimally describe the maturation of size-corrected elimination clearance in this specific population. The final maturation model accounts for the observed clearance maturatation via two distinctive terms: a term accounting for gestational maturation of elimination clearance and a term accounting for postnatal maturation of elimination clearance. This postnatal elimination clearance maturation immediately takes over gestational elimination clearance maturation postpartum and is influenced by GA. Not unexpectedly, BSV not counted for by covariates exceeds that of adult populations11.
Propofol is a highly lipophilic compound characterized by a high hepatic extraction ratio in the adult human. In adults, hepatic metabolic clearance is predominantly mediated by UGT1A9, while minor involvement of multiple CYP isoforms (e.g. CYP2B6 and CYP3A4) has also been observed4. In neonates, due to immature elimination pathways, propofol is a low extraction drug19. Hepatic metabolic clearance is predominantly CYP-mediated, via hydroxylation of propofol to quinol metabolites, due to the limited glucuronidation capacity in this population20,21. Apparently, the minor pathways for hepatic elimination of propofol in adults, represent the proportional major elimination pathways in neonates. The incomplete maturation of metabolic enzymes, both hepatic and extrahepatic phase I and II enzymes, at least partially reflect the observed elimination clearance maturation22,23. Maturational aspects and ontogeny phenomena in neonates are also observed for compounds other than propofol such as morphine (UGT2B7 substrate)24,25and acetaminophen (UGT1A1/UGT1A6 substrate)8. Studying maturational aspects and ontogeny of the human enzymatic repertoire may hence be of importance in addition to drug-specific characteristics and can lead to additional insights into the ontogeny of various phase I and II enzymatic processes in (early) neonatal maturation5,7.
Once the child is born, propofol elimination clearance will rise to adult values. This is reflected in the UGT1A9 ontogony, which has been studied on the level of protein activity, protein expression and mRNA expression, with protein expression catching up to adult levels withing 1 month to 2 years26,27. In addition to maturation/ontogeny, changes in body composition might influence the distribution of propofol and other compounds. Body composition changes, such as the changing composition of fat tissue, and fractional contribution of fat vs. fat free mass to BW, occur continuously during neonatal aging and growth. A covariate effect of PNA on V1 was observed and is most likely explained by these phenomena. A neonate can easily double its BW with accompanying changes in body composition during its first 6 months of life. Algorithms such as the algorithm of Al-Sallami and colleagues28 and the algorithm of Janmahasatian and colleagues29 allow for the imputation of respectively fat free mass and lean bodyweight. However, these algorithms were developed using data collected from subjects outside the neonatal age range. Up to now, no algorithms to impute fat mass, fat-free mass and/or lean bodyweight down to the early neonatal age range, including preterm birth, have been reported.
In conclusion, this study presents, to the best of our knowledge, the first propofol population pharmacokinetic analysis including (pre)term neonates and infants, spanning an age range from 25 weeks to 2 years of postnatal age, accounting for intrauterine (driven by GA) and postnatal (driven by PNA/GA) maturation improves the description of propofol pharmacokinetics in this population. Accounting for the observed PNA-dependent change of BW on V1 improves the model further. The developed model may serve as a prior for propofol dose finding in neonates and infants.