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Population pharmacokinetics of propofol in neonates and infants: gestational and postnatal age to determine clearance maturation
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  • Louis Sandra,
  • Anne Smits,
  • Karel Allegaert,
  • Johan Nicolai,
  • Pieter Annaert,
  • Thomas Bouillon
Louis Sandra
Janssen Pharmaceutica NV
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Anne Smits
University Hospitals Leuven
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Karel Allegaert
Erasmus MC
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Johan Nicolai
UCB Biopharma SRL
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Pieter Annaert
KU Leuven
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Thomas Bouillon
KU Leuven
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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.

Peer review status:ACCEPTED

10 May 2020Submitted to British Journal of Clinical Pharmacology
11 May 2020Submission Checks Completed
11 May 2020Assigned to Editor
16 May 2020Reviewer(s) Assigned
09 Jun 2020Review(s) Completed, Editorial Evaluation Pending
13 Jun 2020Editorial Decision: Revise Major
31 Aug 20201st Revision Received
01 Sep 2020Submission Checks Completed
01 Sep 2020Assigned to Editor
01 Sep 2020Review(s) Completed, Editorial Evaluation Pending
12 Sep 2020Editorial Decision: Accept