Mohammed Rohi Sanoufi1,2, Khadija Guendoul1, Mehdi Oualha3, Léo Froelicher-Bournaud2, Steeve Rouillon2, Seef ABDALLA2, Jean-Marc Treluyer1,2,3, Frantz Foissac, Naïm Bouazza3, Sihem BENABOUD1,2
1Université Paris Cité, Inserm, Pharmacologie et évaluation des thérapeutiques chez l’enfant et la femme enceinte, 2Service de Pharmacologie Clinique, Hôpital Cochin, AP-HP, Groupe Hospitalier Paris Centre, 3Unité de Recherche Clinique Necker-Cochin, AP-HP, Hôpital Tarnier
Introduction: Linezolid (LZD) is a synthetic antibiotic drug from the oxazolidinone class. It is increasingly used in pediatric intensive care units (PICUs) for the treatment of Gram-positive bacterial infections that are multi-resistant to other anti-microbial agents. Unpredictable fluctuations in the pharmacokinetic (PK) variables of patients may necessitate adjustment of the drug dose. The aim of our study was to establish a population pharmacokinetic (PopPK) model for intravenously administered linezolid in critically ill pediatric patients and use it to propose individualized dosing regimens that maximize efficacy while minimizing toxicity. Material and methods: Children aged from birth to 18 years who received LZD as a discontinuous intravenous infusion in the PICUs were included in this study. Plasma concentrations of LZD were measured using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. Population pharmacokinetic analysis was performed using non-linear mixed-effects modelling (Monolix 2023R1). Covariate selection was guided by physiological likelihood and stepwise forward inclusion and backward elimination. Body weight was scaled allometrically. The influence of sex, age, height, baseline platelet count, serum creatinine level, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB), indirect bilirubin (IB), albumin (ALB), C-reactive protein (CRP) concentrations, Liver transplantation, extracorporeal membrane oxygenation (ECMO), comorbidities, reason for hospitalisation, antibiotic dosing regimen, type of infection and pathogens on LZD clearance (CL) and volume of distribution (Vd) were evaluated. Model performance was assessed using diagnostic plots and visual prediction checks. Monte Carlo simulations were performed to estimate probability of target achievement (PTA) for standard and alternative dosing regimens based on established pharmacodynamic (PD) targets (AUC/MIC >80 and Cmin 2-7 mg/L). Results: Fifty-seven patients (median age: 12 years; range: 0.03 to 15.8 years) and 103 linezolid plasma concentrations were included. A one-compartment model with first-order elimination best described linezolid pharmacokinetics. Clearance (CL) and volume of distribution (Vd) were significantly influenced by body weight (allometrically scaled), estimated glomerular filtration rate (eGFR), age, and liver transplant status. According to Monte Carlo simulations, standard dosing regimens (10 mg/kg every 8 h or 600 mg every 12 h for patients >40 kg) failed to achieve the target of minimum concentrations (2–6.3 mg/L) and an optimal AUC/MIC >80 across all patient group. Discussion: The present study highlights the significant inter-individual variability in linezolid pharmacokinetics in critically ill paediatric patients. The findings demonstrate the importance of incorporating physiological covariates, such as renal function and liver transplant status, into dosing decisions. It is evident that standard treatement regimens frequently are suboptimal, and individualised dosing guided by PopPK modelling and therapeutic drug monitoring (TDM) is recommended to ensure sufficient exposure and therapeutic response. This work support to the implementation of model-informed precision dosing strategies in the context of paediatric antimicrobial therapy.
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Reference: PAGE 33 (2025) Abstr 11664 [www.page-meeting.org/?abstract=11664]
Poster: Drug/Disease Modelling - Paediatrics