Population Pharmacokinetics of Anti-infectives in Critically Ill Children

Официальное название

Population Pharmacokinetics and Rationalization of Anti-infectives Administration in Critically Ill Children

Обзор

Concentrations and effects of anti-infectives in critically ill children are unpredictable and the risk of under-exposure may be associated with poor clinical outcomes. In addition, between-subject variability (BSV) is known to be substantial in critically ill children. Rationalisation of anti-infectives in children is therefore desirable. The investigators aim to investigate, using a population approach, the pharmacokinetics (PK) and pharmacodynamics (PD) of anti-infectives including PK/PD targets (fT(%) \> minimal inhibitory concentration (MIC)) and PD endpoints (clinical outcomes) in critically ill children. Covariates The effects of covariates on anti-infectives PK and PK/PDs are investigated in order to better explain the BSV and to ultimately suggest individualized dosage regimens. It will be a prospective PK study including 11 anti-infectives antibiotics. Six blood samples were taken from each patient during dosing interval. The primary PK/ PD targets were anti-infectives concentrations above the MIC of the pathogen at both 50% (50% f T\>MIC) and 100% (100% f T\>MIC) of the dosing interval. The investigators used skewed logistic regression to describe the effect of anti-infectives exposure on patient outcome.

Подробное описание

Background and aims of the study:

Recent studies have suggested a risk of under-exposure to anti-infectives in critically ill adults. This under-exposure may be associated with poor clinical outcomes as well as a delay or incomplete clinical resolution of infection; The dosing regimen of anti-infectives in critically ill children is usually based on weight (i.e. mg per Kg). However, between-subject variability is known to be substantial in children and even more so in critical illness; As a result, concentrations and effects of anti-infectives are unpredictable and the risk of under- or over-exposure is thus genuine and considerable. Rationalisation of anti-infectives in children is therefore desirable.

The purpose of the present study is to investigate, using a population approach, the pharmacokinetics (PK) and pharmacodynamics (PD) of intravenous anti-infectives including usual PK/PD targets (fT(%) \> minimal inhibitory concentration (MIC)) and PD endpoints (clinical outcomes) in critically ill children. The effects of developmental and other factors related to critical illness on anti-infectives PK and PK/PDs are investigated in order to better explain the observed between-subject variabilities and to ultimately suggest individualized dosage regimens.

This prospective study will be conducted in six paediatric services of Public Hospitals in Paris, France

Intervention:

Patient selection will take place in the 6 paediatric services. The senior physician proposes the study to holders of parental authority whose child receives or will receive anti-infectives during its follow-up or hospitalization.

The senior physician will give a briefing note to the holders of parental authority, and if the child is able to understand the information. The non-oral opposition for the retrieval and analysis of data will be collected.

No intervention or no charge will be made for this study.

Вмешательства

• Другое Pharmacokinetics

Первичные конечные точки

• anti-infectives concentration [Срок оценки: until 28 days]

Вторичные конечные точки (3)

• number of identified or suspected pathogen [Срок оценки: until 28 days]
• composite measure of the health condition [Срок оценки: until 28 days]
• predictive variables of underdosing/overdosing of antiinfectives and biological evolution [Срок оценки: until 28 days]

Критерии участия

Критерии включения

• Minor patient requiring the administration of an anti-infective belonging to the following classes : β-lactam antibiotics; aminoglycosides, glycopeptides; fluoroquinolones; other antibiotics (daptomycin, rifampin, trimethoprim, sulfamethoxazole, clarithromycin); fungal; antivirals, during its follow-up or hospitalization

Критерии исключения

• Patient and parents having notified to the doctor that they refuse data recovery.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Франция · 1 центр

• Hospital Necker - Enfants Malades (Public Hospitals of Paris) — Paris

Публикации

• Arsene A, Oualha M, Rambaud J, Benaboud S, Urien S, Grimaud M, Renolleau S, Leger PL, Hirt D, Treluyer JM, Beranger A. Piperacillin Population Pharmacokinetics in Children Supported With Extracorporeal Membrane Oxygenation. Pediatr Crit Care Med. 2026 Aug 6. doi: 10.1097/PCC.0000000000004016. Online ahead of print. PMID 42560139
• Berthaud R, Urien S, Krid S, Foissac F, Oualha M, Thy M, Boyer O, Beranger A, Hirt D, Benaboud S, Treluyer J-M, Bouazza N. Cefazolin population pharmacokinetics in children undergoing maintenance hemodialysis for kidney failure. Antimicrob Agents Chemother. 2025 Nov 5;69(11):e0045125. doi: 10.1128/aac.00451-25. Epub 2025 Oct 2. PMID 41036866
• Marsaux A, Leger PL, Rambaud J, Bille E, Renolleau S, Treluyer JM, Gana I, Lorrot M, Grimaud M, Toubiana J, Beranger A, Benaboud S, Oualha M. Beta-Lactam Antibiotic Exposure During Pediatric Extracorporeal Membrane Oxygenation: Retrospective Cohort Analysis of Drug Levels Using Standard Dosing, 2018-2020. Pediatr Crit Care Med. 2024 Dec 1;25(12):1127-1137. doi: 10.1097/PCC.0000000000003605. Epub 2 PMID 39630067
• Collignon C, de Marcellus C, Oualha M, Neuranter V, Heilbronner C, Hirt D. Pharmacokinetic profile of acyclovir in a child receiving continuous kidney replacement therapy for acute liver failure. Pediatr Nephrol. 2023 Oct;38(10):3493-3497. doi: 10.1007/s00467-023-05881-6. Epub 2023 Jan 27. PMID 36702934
• de Cacqueray N, Boujaafar S, Bille E, Moulin F, Gana I, Benaboud S, Hirt D, Beranger A, Toubiana J, Renolleau S, Treluyer JM, Oualha M. Therapeutic Drug Monitoring of Antibiotics in Critically Ill Children: An Observational Study in a Pediatric Intensive Care Unit. Ther Drug Monit. 2022 Apr 1;44(2):319-327. doi: 10.1097/FTD.0000000000000918. PMID 35292609
• Nguyen T, Oualha M, Briand C, Bendavid M, Beranger A, Benaboud S, Treluyer JM, Zheng Y, Foissac F, Winter S, Gana I, Boujaafar S, Lopez V, Berthaud R, Demir Z, Bouazza N, Hirt D. Population Pharmacokinetics of Intravenous Ganciclovir and Oral Valganciclovir in a Pediatric Population To Optimize Dosing Regimens. Antimicrob Agents Chemother. 2021 Feb 17;65(3):e02254-20. doi: 10.1128/AAC.02254-20. Pr PMID 33318012
• Abdalla S, Briand C, Oualha M, Bendavid M, Beranger A, Benaboud S, Treluyer JM, Zheng Y, Capito C, Demir Z, Foissac F, Winter S, Gana I, Boujaafar S, Bouazza N, Hirt D. Population Pharmacokinetics of Intravenous and Oral Acyclovir and Oral Valacyclovir in Pediatric Population To Optimize Dosing Regimens. Antimicrob Agents Chemother. 2020 Nov 17;64(12):e01426-20. doi: 10.1128/AAC.01426-20. Print 20 PMID 32988829
• Beranger A, Benaboud S, Urien S, Moulin F, Bille E, Lesage F, Zheng Y, Genuini M, Gana I, Renolleau S, Hirt D, Treluyer JM, Oualha M. Piperacillin Population Pharmacokinetics and Dosing Regimen Optimization in Critically Ill Children with Normal and Augmented Renal Clearance. Clin Pharmacokinet. 2019 Feb;58(2):223-233. doi: 10.1007/s40262-018-0682-1. PMID 29862466

Идентификаторы

NCT: NCT02539407 · 2014-01-08

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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