Population pharmacokinetics of meropenem in critically ill children with different renal functions

• Published in: European journal of clinical pharmacology Vol. 76; no. 1; pp. 61 - 71
• Main Authors: Rapp, Mélanie, Urien, Saïk, Foissac, Frantz, Béranger, Agathe, Bouazza, Naïm, Benaboud, Sihem, Bille, Emmanuelle, Zheng, Yi, Gana, Inès, Moulin, Florence, Lesage, Fabrice, Renolleau, Sylvain, Tréluyer, Jean Marc, Hirt, Déborah, Oualha, Mehdi
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2020; Springer Nature B.V
• Subjects: Antibiotics; Biomedical and Life Sciences; Biomedicine; Body weight; Children; Chromatography; Creatinine; Epidermal growth factor receptors; Extracorporeal membrane oxygenation; Glomerular filtration rate; High-performance liquid chromatography; Intensive care; Kidneys; Laboratories; Meropenem; Minimum inhibitory concentration; Patients; Pediatrics; Pharmacokinetics; Pharmacokinetics and Disposition; Pharmacology/Toxicology; Population; Renal failure; Pharmacokinetics; Critically ill children; Meropenem
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-019-02761-7

Purpose We aimed to develop a meropenem population pharmacokinetic (PK) model in critically ill children and simulate dosing regimens in order to optimize patient exposure. Methods Meropenem plasma concentration was quantified by high-performance liquid chromatography. Meropenem PK was investigated using a non-linear mixed-effect modeling approach. Results Forty patients with an age of 16.8 (1.4–187.2) months, weight of 9.1 (3.8–59) kg, and estimated glomerular filtration rate (eGFR) of 151 (19–440) mL/min/1.73 m 2 were included. Eleven patients received continuous replacement renal therapy (CRRT). Concentration-time courses were best described by a two-compartment model with first-order elimination. Body weight (BW), eGFR, and CRRT were covariates explaining the between-subject variabilities on central/peripheral volume of distribution (V1/V2), inter-compartment clearance ( Q ), and clearance (CL): V1 i  = V1 pop × (BW/70) 1 , Q i  =  Q pop × (BW/70) 0.75 , V2 i  = V2 pop × (BW/70) 1 , CL i  = (CL pop × (BW/70) 0.75 ) × (eGFR/100) 0.378 ) for patients without CRRT and CL i  = (CL pop × (BW/70) 0.75 ) × 0.9 for patients with CRRT, where CL pop , V1 pop , Q pop , and V2 pop are 6.82 L/h, 40.6 L, 1 L/h, and 9.2 L respectively normalized to a 70-kg subject. Continuous infusion, 60 and 120 mg/kg per day, is the most adequate dosing regimen to attain the target of 50% f T >  MIC and 100% f T >  MIC for patients infected by bacteria with high minimum inhibitory concentration (MIC) value (> 4 mg/L) without risk of accumulation except in children with severe renal failure. Conclusion Continuous infusion allows reaching the f T >  MIC targets safely in children with normal or increased renal clearance.