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

Janneke M. Brussee, Nienke J. Vet, Elke H.J. Krekels, Abraham J. Valkenburg, Evelyne Jacqz-Aigrain, Joop M.A. van Gerven, Eleonora L. Swart, Johannes N. van den Anker, Dick Tibboel, Matthijs de Hoog, Saskia N. de Wildt, Catherijne A.J. Knibbe

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)358-368
Number of pages11
JournalBritish Journal of Clinical Pharmacology
Volume84
Issue number2
DOIs
Publication statusPublished - 1 Feb 2018

Cite this

Brussee, J. M., Vet, N. J., Krekels, E. H. J., Valkenburg, A. J., Jacqz-Aigrain, E., van Gerven, J. M. A., ... Knibbe, C. A. J. (2018). Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure. British Journal of Clinical Pharmacology, 84(2), 358-368. https://doi.org/10.1111/bcp.13459
Brussee, Janneke M. ; Vet, Nienke J. ; Krekels, Elke H.J. ; Valkenburg, Abraham J. ; Jacqz-Aigrain, Evelyne ; van Gerven, Joop M.A. ; Swart, Eleonora L. ; van den Anker, Johannes N. ; Tibboel, Dick ; de Hoog, Matthijs ; de Wildt, Saskia N. ; Knibbe, Catherijne A.J. / Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure. In: British Journal of Clinical Pharmacology. 2018 ; Vol. 84, No. 2. pp. 358-368.
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title = "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 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.",
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author = "Brussee, {Janneke M.} and Vet, {Nienke J.} and Krekels, {Elke H.J.} and Valkenburg, {Abraham J.} and Evelyne Jacqz-Aigrain and {van Gerven}, {Joop M.A.} and Swart, {Eleonora L.} and {van den Anker}, {Johannes N.} and Dick Tibboel and {de Hoog}, Matthijs and {de Wildt}, {Saskia N.} and Knibbe, {Catherijne A.J.}",
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Brussee, JM, Vet, NJ, Krekels, EHJ, Valkenburg, AJ, Jacqz-Aigrain, E, van Gerven, JMA, Swart, EL, van den Anker, JN, Tibboel, D, de Hoog, M, de Wildt, SN & Knibbe, CAJ 2018, 'Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure' British Journal of Clinical Pharmacology, vol. 84, no. 2, pp. 358-368. https://doi.org/10.1111/bcp.13459

Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure. / Brussee, Janneke M.; Vet, Nienke J.; Krekels, Elke H.J.; Valkenburg, Abraham J.; Jacqz-Aigrain, Evelyne; van Gerven, Joop M.A.; Swart, Eleonora L.; van den Anker, Johannes N.; Tibboel, Dick; de Hoog, Matthijs; de Wildt, Saskia N.; Knibbe, Catherijne A.J.

In: British Journal of Clinical Pharmacology, Vol. 84, No. 2, 01.02.2018, p. 358-368.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure

AU - Brussee, Janneke M.

AU - Vet, Nienke J.

AU - Krekels, Elke H.J.

AU - Valkenburg, Abraham J.

AU - Jacqz-Aigrain, Evelyne

AU - van Gerven, Joop M.A.

AU - Swart, Eleonora L.

AU - van den Anker, Johannes N.

AU - Tibboel, Dick

AU - de Hoog, Matthijs

AU - de Wildt, Saskia N.

AU - Knibbe, Catherijne A.J.

PY - 2018/2/1

Y1 - 2018/2/1

N2 - 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.

AB - 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.

KW - children

KW - cytochrome P450

KW - drug metabolism

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U2 - 10.1111/bcp.13459

DO - 10.1111/bcp.13459

M3 - Article

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JF - British Journal of Clinical Pharmacology

SN - 0306-5251

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