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

Author(s):
Brussee, J.M.; Vet, N.J.; Elke, H.J. Krekels; Valkenburg, A.J.; Jacqz-Aigrain, E.; Gerven, J.M.A. van; Swart, E.L.; Anker, J.N. van den; Tibboel, D.; Hoog, M. de; Wildt, S.N. de; Knibbe, C.A.J.
Published
2017
Publication type
Article / Letter to editor

Abstract

Aims: Inflammation and organ failure have been reported to impact

cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill

children. Our aim was to evaluate a previously developed population

pharmacokinetic model in both 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 externally evaluated in 136 individuals, including (pre)term neonates, infants, children, and adults (body weight 0.77-90 kg, CRP 0.1-341 mg/L and 0-4 failing organs) using graphical and numerical diagnostics. Results: The pharmacokinetic model predicted midazolam clearance and plasma concentrations without bias in post-operative or critically ill paediatric patients and term neonates (median prediction error (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.

childrendrug metabolismcytochrome P450
Date issued
2017
Is part of
British Journal of Clinical Pharmacology
hdl
1887/56188