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Predicting CYP3A‐mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure
Author(s) -
Brussee Janneke M.,
Vet Nienke J.,
Krekels Elke H. J.,
Valkenburg Abraham J.,
JacqzAigrain Evelyne,
Gerven Joop M. A.,
Swart Eleonora L.,
Anker Johannes N.,
Tibboel Dick,
Hoog Matthijs,
Wildt Saskia N.,
Knibbe Catherijne A. J.
Publication year - 2018
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.13459
Subject(s) - medicine , dosing , midazolam , critically ill , pharmacokinetics , cyp3a , population , pediatrics , intensive care medicine , anesthesia , physiology , cytochrome p450 , metabolism , environmental health , sedation
Aims 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. Methods 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. Results 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%). Conclusion 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 in term neonates, children and adults with varying levels of critical illness, including healthy adults, but not for extrapolation to preterm neonates.