Abstract
Develop a population pharmacokinetic model describing propofol pharmacokinetics in (pre)term neonates and infants, that can be used for precision dosing (e.g. during target-controlled infusion) of propofol in this population. A nonlinear mixed effects pharmacokinetic analysis (Monolix 2018R2) was performed, based on a pooled study population in 107 (pre)term neonates and infants. In total, 836 blood samples were collected from 66 (pre)term neonates and 41 infants originating from 3 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 min-max range). A 3-compartment structural model was identified and the effect of BW was modelled using fixed allometric exponents. Elimination clearance maturation was modelled accounting for the maturational effect on elimination clearance until birth (by gestational age [GA]) and postpartum (by PNA and GA). The extrapolated adult (70 kg) population propofol elimination clearance (1.64 L min-1 , estimated relative standard error = 6.02%) is in line with estimates from previous population pharmacokinetic studies. Empirical scaling of BW on the central distribution volume in function of PNA improved the model fit. 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 central distribution volume. The developed model may serve as a prior for propofol dose finding and target-controlled infusion in (preterm) neonates.
Highlights
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record
As a consequence, dosing recommendations for propofol in neonates and infants are limited, at best based on manual infusion regimens for target controlled infusion (TCI)[2]
While enzyme maturation is largely complete at 2 years of postnatal age (PNA), this remains a prominent determinant of drug metabolism in neonates[7,8]
Summary
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Propofol is frequently used for induction of anesthesia and procedural sedation in (pre)term neonates and infants, despite being off label in this population. Being a UGT1A9 and CYP2C9/2B6 substrate, maturational on top of allometry effects have to be accounted for to describe the pharmacokinetics in this population. Former propofol pharmacokinetic analyses account for elimination clearance maturation using a postmenstrual age (PMA) dependent Emax-type maturation model. A propofol population pharmacokinetic analysis performed on a large dataset, originating from 107 children under the age of 2 years, including a significant proportion of preterm and term neonates
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