■ 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.