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

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) <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.

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