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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064165%3A_____%2F25%3A10504117" target="_blank" >RIV/00064165:_____/25:10504117 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11110/25:10504117

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=kxYJfYCtV4" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=kxYJfYCtV4</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1111/pan.70050" target="_blank" >10.1111/pan.70050</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30209 - Paediatrics

Projekt

—

Návaznosti

V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Paediatric Anaesthesia

ISSN

1155-5645

e-ISSN

1460-9592

Svazek periodika

35

Číslo periodika v rámci svazku

12

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

10

Strana od-do

1053-1062

Kód UT WoS článku

001586371100001

EID výsledku v databázi Scopus

2-s2.0-105021324530