Population pharmacokinetics of propofol in neonates and infants:
gestational and postnatal age to determine clearance maturation
Abstract
Aims: Develop a population pharmacokinetic model describing propofol
pharmacokinetics in (pre)term neonates and infants, that can be used for
precision dosing of propofol in this population. Methods: A non-linear
mixed effects pharmacokinetic analysis (Monolix 2018R2) was performed,
based on a pooled study population in 107 (pre)term neonates and
infants. Results: 836 blood samples were collected from 66 (pre)term
neonates and 41 infants originating from three studies. Body weight (BW)
of the pooled study population was 3.050 (0.580 – 11.440) kg,
postmenstrual age (PMA) was 36.56 (27.00 – 43.00) weeks and postnatal
age (PNA) was 1.14 (0 – 104.00) weeks (median and range). A three
compartment structural model was identified and the effect of BW was
modeled using fixed allometric exponents. Elimination clearance
maturation was modeled accounting for the maturational effect on
elimination clearance until birth (by GA) and postpartum (by PNA/GA).
The extrapolated adult (70 kg) population propofol elimination clearance
(1.63 L min-1) is in line with estimates from previous population
pharmacokinetic studies. Empirical scaling of BW on the central
distribution volume (V1) in function of PNA improved the
model fit. Conclusions: It is recommended to describe elimination
clearance maturation by GA and PNA instead of PMA on top of size effects
when analyzing propofol pharmacokinetics in populations including
preterm neonates. Changes in body composition in addition to weight
changes or other physio-anatomical changes may explain the changes in
V1. The developed model may serve as a prior for
propofol dose finding in (preterm) neonates.