Pharmacokinetic and Pharmacodynamic Modeling of Clonidine and Midazolam for Sedation in Pediatric Intensive Care

Maddlie Bardol; Yucheng Sheng; CloSed Consortium; Manuel Baarslag; Adriana Ceci; Frank Dörje; Mari Liis Ilmoja; Peter Larsson; Per Arne Lönnqvist; Tuuli Methsvat; Pavla Pokorna; Wolfgang Rascher; Joost van Rosmalen; Michael Schroth; Alessandra Simonetti; Dick Tibboel; Irmgard Toni; Catherine Tuleu; Thomas M.K. Völkl; Brian J. Anderson; Stefan Wimmer; Joseph F. Standing; Antje Neubert

doi:10.1111/pan.70050

Pharmacokinetic and Pharmacodynamic Modeling of Clonidine and Midazolam for Sedation in Pediatric Intensive Care

Maddlie Bardol^*
, Yucheng Sheng
, CloSed Consortium
, Manuel Baarslag
, Adriana Ceci
, Frank Dörje
, Mari Liis Ilmoja
, Peter Larsson
, Per Arne Lönnqvist
, Tuuli Methsvat
, Pavla Pokorna
, Wolfgang Rascher
, Joost van Rosmalen
, Michael Schroth
, Alessandra Simonetti
, Dick Tibboel
, Irmgard Toni
, Catherine Tuleu
, Thomas M.K. Völkl
, Brian J. Anderson

Stefan Wimmer, Joseph F. Standing, Antje Neubert

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background:

Clonidine and midazolam are routinely used in the pediatric intensive care unit for pain and sedation management, but target concentration and optimal dose are poorly defined for both drugs. The CloSed study is a multicenter, double-blind, randomized, active-controlled noninferiority trial with a 1:1 randomization between clonidine and midazolam. Aims: Data from the prematurely terminated CloSed trial were used to study the population pharmacokinetic–pharmacodynamic relationships for clonidine and midazolam to inform the optimal use of both drugs in mechanically ventilated children.

Methods:

Twenty-eight patients (0–6 years) were included; 13 received midazolam, and 15 received clonidine. Morphine was administered to all patients as background analgesia. A total of 317 and 306 observed COMFORT-B scores for midazolam and clonidine, respectively, were available to build the pharmacokinetic–pharmacodynamic model. Pharmacokinetic models were developed using findings from previously published pharmacokinetic studies to augment the trial data. A one-compartment model described clonidine pharmacokinetics, while a single compartment for midazolam and its metabolite described its pharmacokinetics. A joint inhibitory sigmoid model that included a postanesthesia effect was used to describe the concentration–effect relationship, using the COMFORT-B score as the pharmacodynamic endpoint.

Results:

The final models adequately described the observed data. Simulations based on the final models showed that a clonidine dose of 4 μg/kg loading dose followed by a 3 μg/kg/h infusion, and a midazolam dose of 200 μg/kg loading dose followed by a 200 μg/kg/h infusion would be required to achieve adequate sedation.

Conclusion:

The CloSed data suggest that higher doses of clonidine and midazolam than are commonly used in clinical practice should be considered to provide adequate sedation in critically ill children.

Original language	English
Pages (from-to)	1053-1062
Number of pages	10
Journal	Paediatric Anaesthesia
Volume	35
Issue number	12
DOIs	https://doi.org/10.1111/pan.70050
Publication status	Published - Dec 2025

Bibliographical note

Publisher Copyright:
© 2025 The Author(s). Pediatric Anesthesia published by John Wiley & Sons Ltd.

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Pharmacokinetic and Pharmacodynamic Modeling of Clonidine and Midazolam for Sedation in Pediatric Intensive CareFinal published version, 1.34 MBLicence: CC BY

Cite this

Bardol, M., Sheng, Y., CloSed Consortium, Baarslag, M., Ceci, A., Dörje, F., Ilmoja, M. L., Larsson, P., Lönnqvist, P. A., Methsvat, T., Pokorna, P., Rascher, W., van Rosmalen, J., Schroth, M., Simonetti, A., Tibboel, D., Toni, I., Tuleu, C., Völkl, T. M. K., ... Neubert, A. (2025). Pharmacokinetic and Pharmacodynamic Modeling of Clonidine and Midazolam for Sedation in Pediatric Intensive Care. Paediatric Anaesthesia, 35(12), 1053-1062. https://doi.org/10.1111/pan.70050

@article{048ee839cc7641c281e05c766b34164a,

title = "Pharmacokinetic and Pharmacodynamic Modeling of Clonidine and Midazolam for Sedation in Pediatric Intensive Care",

abstract = "Background: Clonidine and midazolam are routinely used in the pediatric intensive care unit for pain and sedation management, but target concentration and optimal dose are poorly defined for both drugs. The CloSed study is a multicenter, double-blind, randomized, active-controlled noninferiority trial with a 1:1 randomization between clonidine and midazolam. Aims: Data from the prematurely terminated CloSed trial were used to study the population pharmacokinetic–pharmacodynamic relationships for clonidine and midazolam to inform the optimal use of both drugs in mechanically ventilated children. Methods: Twenty-eight patients (0–6 years) were included; 13 received midazolam, and 15 received clonidine. Morphine was administered to all patients as background analgesia. A total of 317 and 306 observed COMFORT-B scores for midazolam and clonidine, respectively, were available to build the pharmacokinetic–pharmacodynamic model. Pharmacokinetic models were developed using findings from previously published pharmacokinetic studies to augment the trial data. A one-compartment model described clonidine pharmacokinetics, while a single compartment for midazolam and its metabolite described its pharmacokinetics. A joint inhibitory sigmoid model that included a postanesthesia effect was used to describe the concentration–effect relationship, using the COMFORT-B score as the pharmacodynamic endpoint. Results: The final models adequately described the observed data. Simulations based on the final models showed that a clonidine dose of 4 μg/kg loading dose followed by a 3 μg/kg/h infusion, and a midazolam dose of 200 μg/kg loading dose followed by a 200 μg/kg/h infusion would be required to achieve adequate sedation. Conclusion: The CloSed data suggest that higher doses of clonidine and midazolam than are commonly used in clinical practice should be considered to provide adequate sedation in critically ill children.",

author = "Maddlie Bardol and Yucheng Sheng and \{CloSed Consortium\} and Manuel Baarslag and Adriana Ceci and Frank D{\"o}rje and Ilmoja, \{Mari Liis\} and Peter Larsson and L{\"o}nnqvist, \{Per Arne\} and Tuuli Methsvat and Pavla Pokorna and Wolfgang Rascher and \{van Rosmalen\}, Joost and Michael Schroth and Alessandra Simonetti and Dick Tibboel and Irmgard Toni and Catherine Tuleu and V{\"o}lkl, \{Thomas M.K.\} and Anderson, \{Brian J.\} and Stefan Wimmer and Standing, \{Joseph F.\} and Antje Neubert",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s). Pediatric Anesthesia published by John Wiley \& Sons Ltd.",

year = "2025",

month = dec,

doi = "10.1111/pan.70050",

language = "English",

volume = "35",

pages = "1053--1062",

journal = "Paediatric Anaesthesia",

issn = "1155-5645",

publisher = "John Wiley \& Sons Inc.",

number = "12",

}

Bardol, M, Sheng, Y, CloSed Consortium, Baarslag, M, Ceci, A, Dörje, F, Ilmoja, ML, Larsson, P, Lönnqvist, PA, Methsvat, T, Pokorna, P, Rascher, W, van Rosmalen, J, Schroth, M, Simonetti, A, Tibboel, D, Toni, I, Tuleu, C, Völkl, TMK, Anderson, BJ, Wimmer, S, Standing, JF & Neubert, A 2025, 'Pharmacokinetic and Pharmacodynamic Modeling of Clonidine and Midazolam for Sedation in Pediatric Intensive Care', Paediatric Anaesthesia, vol. 35, no. 12, pp. 1053-1062. https://doi.org/10.1111/pan.70050

TY - JOUR

T1 - Pharmacokinetic and Pharmacodynamic Modeling of Clonidine and Midazolam for Sedation in Pediatric Intensive Care

AU - Bardol, Maddlie

AU - Sheng, Yucheng

AU - CloSed Consortium

AU - Baarslag, Manuel

AU - Ceci, Adriana

AU - Dörje, Frank

AU - Ilmoja, Mari Liis

AU - Larsson, Peter

AU - Lönnqvist, Per Arne

AU - Methsvat, Tuuli

AU - Pokorna, Pavla

AU - Rascher, Wolfgang

AU - van Rosmalen, Joost

AU - Schroth, Michael

AU - Simonetti, Alessandra

AU - Tibboel, Dick

AU - Toni, Irmgard

AU - Tuleu, Catherine

AU - Völkl, Thomas M.K.

AU - Anderson, Brian J.

AU - Wimmer, Stefan

AU - Standing, Joseph F.

AU - Neubert, Antje

PY - 2025/12

Y1 - 2025/12

N2 - Background: Clonidine and midazolam are routinely used in the pediatric intensive care unit for pain and sedation management, but target concentration and optimal dose are poorly defined for both drugs. The CloSed study is a multicenter, double-blind, randomized, active-controlled noninferiority trial with a 1:1 randomization between clonidine and midazolam. Aims: Data from the prematurely terminated CloSed trial were used to study the population pharmacokinetic–pharmacodynamic relationships for clonidine and midazolam to inform the optimal use of both drugs in mechanically ventilated children. Methods: Twenty-eight patients (0–6 years) were included; 13 received midazolam, and 15 received clonidine. Morphine was administered to all patients as background analgesia. A total of 317 and 306 observed COMFORT-B scores for midazolam and clonidine, respectively, were available to build the pharmacokinetic–pharmacodynamic model. Pharmacokinetic models were developed using findings from previously published pharmacokinetic studies to augment the trial data. A one-compartment model described clonidine pharmacokinetics, while a single compartment for midazolam and its metabolite described its pharmacokinetics. A joint inhibitory sigmoid model that included a postanesthesia effect was used to describe the concentration–effect relationship, using the COMFORT-B score as the pharmacodynamic endpoint. Results: The final models adequately described the observed data. Simulations based on the final models showed that a clonidine dose of 4 μg/kg loading dose followed by a 3 μg/kg/h infusion, and a midazolam dose of 200 μg/kg loading dose followed by a 200 μg/kg/h infusion would be required to achieve adequate sedation. Conclusion: The CloSed data suggest that higher doses of clonidine and midazolam than are commonly used in clinical practice should be considered to provide adequate sedation in critically ill children.

AB - Background: Clonidine and midazolam are routinely used in the pediatric intensive care unit for pain and sedation management, but target concentration and optimal dose are poorly defined for both drugs. The CloSed study is a multicenter, double-blind, randomized, active-controlled noninferiority trial with a 1:1 randomization between clonidine and midazolam. Aims: Data from the prematurely terminated CloSed trial were used to study the population pharmacokinetic–pharmacodynamic relationships for clonidine and midazolam to inform the optimal use of both drugs in mechanically ventilated children. Methods: Twenty-eight patients (0–6 years) were included; 13 received midazolam, and 15 received clonidine. Morphine was administered to all patients as background analgesia. A total of 317 and 306 observed COMFORT-B scores for midazolam and clonidine, respectively, were available to build the pharmacokinetic–pharmacodynamic model. Pharmacokinetic models were developed using findings from previously published pharmacokinetic studies to augment the trial data. A one-compartment model described clonidine pharmacokinetics, while a single compartment for midazolam and its metabolite described its pharmacokinetics. A joint inhibitory sigmoid model that included a postanesthesia effect was used to describe the concentration–effect relationship, using the COMFORT-B score as the pharmacodynamic endpoint. Results: The final models adequately described the observed data. Simulations based on the final models showed that a clonidine dose of 4 μg/kg loading dose followed by a 3 μg/kg/h infusion, and a midazolam dose of 200 μg/kg loading dose followed by a 200 μg/kg/h infusion would be required to achieve adequate sedation. Conclusion: The CloSed data suggest that higher doses of clonidine and midazolam than are commonly used in clinical practice should be considered to provide adequate sedation in critically ill children.

UR - https://www.scopus.com/pages/publications/105021324530

U2 - 10.1111/pan.70050

DO - 10.1111/pan.70050

M3 - Article

C2 - 41045026

AN - SCOPUS:105021324530

SN - 1155-5645

VL - 35

SP - 1053

EP - 1062

JO - Paediatric Anaesthesia

JF - Paediatric Anaesthesia

IS - 12

ER -

Pharmacokinetic and Pharmacodynamic Modeling of Clonidine and Midazolam for Sedation in Pediatric Intensive Care

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