Population pharmacokinetics of meropenem in critically ill children with different renal functions
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We aimed to develop a meropenem population pharmacokinetic (PK) model in critically ill children and simulate dosing regimens in order to optimize patient exposure.
Meropenem plasma concentration was quantified by high-performance liquid chromatography. Meropenem PK was investigated using a non-linear mixed-effect modeling approach.
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 m2 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): V1i = V1pop × (BW/70)1, Qi = Qpop × (BW/70)0.75, V2i = V2pop × (BW/70)1, CLi = (CLpop × (BW/70)0.75) × (eGFR/100)0.378) for patients without CRRT and CLi = (CLpop × (BW/70)0.75) × 0.9 for patients with CRRT, where CLpop, V1pop, Qpop, and V2pop 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% fT > MIC and 100% fT > 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.
Continuous infusion allows reaching the fT > MIC targets safely in children with normal or increased renal clearance.
KeywordsMeropenem Pharmacokinetics Critically ill children
Augmented renal clearance
Bayesian information criteria
Continuous renal replacement therapy
Extracorporeal membrane oxygenation
European Medicines Agency
Estimated glomerular filtration rate
Minimum inhibitory concentration
Pediatric intensive care unit
Probability of target attainment
Volume of distribution
The authors thank the PICU team (physicians and nurses) that selected the children and collected the samples, making this work possible. They also thank the pharmacology laboratory of the Cochin Teaching Hospital, which analyzed the samples.
Authors’ individual contributions
MR collected the data and drafted the manuscript. MO conceived the study and critically revised the manuscript. IG and YZ performed assay analysis. EB identified pathogen agents and related MIC. SU, FF, NB, SB, and DH contributed to acquisition, analysis, and interpretation and also critically revised the manuscript. JMT and SR contributed to conception and design. FL and FM critically revised the manuscript.
Mélanie Rapp received a grant from the “société française de pédiatrie” for a 1-year research fellowship in the EA7323. The research study received funds from Necker Hospital “financement interne.”
Compliance with ethical standards
The Ethics Committee of Necker Hospital approved the study, which was registered at www.clinicaltrials.gov (NCT02539407). Before any inclusion, consent was obtained from children’s parent(s).
Conflict of interest
The authors declare that they have no conflict of interest.
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