■ INTRODUCTION
Propofol is frequently used for induction of anesthesia and procedural
sedation, including off label use in (pre)term neonates. Despite its
availability for almost 30 years, neonatal propofol pharmacokinetics
remain poorly studied1. Propofol is only approved for
clinical use in children 3 years of age or older2.
Propofol is a lipophilic compound that undergoes hepatic metabolism via
hydroxylation by cytochrome P450 (CYP) isoforms (CYP2B6 and CYP3A4) and
glucuronidation by 5’-diphospho-glucuronosyltransferase 1A9
(UGT1A9)3,4. Differences in the abundance and activity
of these enzymes between different age groups are reported in
literature5. Therefore, age-dependency of size
adjusted pharmacokinetic parameters (maturation) was reported earlier,
and was anticipated in the current analysis. Enzyme maturation is
largely complete at 2 years of age, but a prominent determinant of drug
metabolism in neonates6,7. Maturation of propofol
elimination clearance in neonates has been modeled based on
postmenstrual age (PMA), the sum of gestational age (GA) and postnatal
age (PNA), not always separately accounting for changes in body
size/weight8. These simplifications may not be fully
appropriate for preterm neonates. Age and weight correlate substantially
in this population and may confound covariate
effects9. In addition, pre and postnatal maturation
are not expected to follow the same trajectory. A postmenstrual age of
38 weeks most likely reflects different maturation in a 8 weeks old
neonate born after 30 weeks of gestation versus a full term neonate
immediately after birth. Since currently available population
pharmacokinetic models for propofol in neonates lack granularity in this
regard, we expanded these models in order to optimally capturing size
and maturation effects8,10,11.