Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure

British Journal of Clinical Pharmacology
Janneke M BrusseeCatherijne A J Knibbe

Abstract

Inflammation and organ failure have been reported to have an impact on cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model both in critically ill children and other populations, in order to allow the model to be used to guide dosing in clinical practice. The model was evaluated externally in 136 individuals, including (pre)term neonates, infants, children and adults (body weight 0.77-90 kg, C-reactive protein level 0.1-341 mg l-1 and 0-4 failing organs) using graphical and numerical diagnostics. The pharmacokinetic model predicted midazolam clearance and plasma concentrations without bias in postoperative or critically ill paediatric patients and term neonates [median prediction error (MPE) <30%]. Using the model for extrapolation resulted in well-predicted clearance values in critically ill and healthy adults (MPE <30%), while clearance in preterm neonates was over predicted (MPE >180%). The recently published pharmacokinetic model for midazolam, quantifying the influence of maturation, inflammation and organ failure in children, yields unbiased clearance predictions and can therefore be used for dosing instructions...Continue Reading

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Citations

Apr 11, 2018·British Journal of Clinical Pharmacology·Shaun S KumarCatherine M Sherwin
Sep 25, 2018·Journal of Clinical Pharmacology·John van den AnkerGregory L Kearns
Oct 17, 2019·Clinical Pharmacology and Therapeutics·Alexander A VinksKevin R Dufendach
Nov 20, 2019·European Journal of Clinical Pharmacology·Suzan C M Cochius-den OtterBirgit C P Koch
Jul 23, 2020·Pediatric Research·Robert B FlintUNKNOWN DINO Research Group
Sep 11, 2019·Journal of Clinical Pharmacology·Karel Allegaert, John van den Anker
Jul 14, 2020·Pharmacology & Therapeutics·Françoise Stanke-LabesqueUNKNOWN French Society of Pharmacology and Therapeutics
Mar 24, 2021·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Zahari VinarovPatrick Augustijns
Oct 1, 2021·The Annals of Pharmacotherapy·C Michael White

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Methods Mentioned

BETA
sedation

Software Mentioned

NONMEM
NPDE
R
studio

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