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

  • Mélanie RappEmail author
  • Saïk Urien
  • Frantz Foissac
  • Agathe Béranger
  • Naïm Bouazza
  • Sihem Benaboud
  • Emmanuelle Bille
  • Yi Zheng
  • Inès Gana
  • Florence Moulin
  • Fabrice Lesage
  • Sylvain Renolleau
  • Jean Marc Tréluyer
  • Déborah Hirt
  • Mehdi Oualha
Pharmacokinetics and Disposition



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.


Meropenem Pharmacokinetics Critically ill children 



Augmented renal clearance


Bayesian information criteria


Between-subject variability


Body weight




C-reactive protein


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.

Funding information

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 (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.

Supplementary material

228_2019_2761_MOESM1_ESM.docx (13 kb)
ESM 1 Supplemental material (Assessment of meropenem risk of toxicity) Time course concentration for four groups defined according to renal function (A,B,C,D) with various infusion modalities. (dotted blue: 20 mg/kg every 8 h as a 20-min infusion, dotted red: 40 mg/kg every 8 h as a 20-min infusion, dotted dark green: 20 mg/kg every 8 h as a 3-h infusion, blue: 60 mg/kg per day as a continuous infusion after a bolus of 20 mg/kg, red: 120 mg/kg per day as a continuous infusion after a bolus of 20 mg/kg). Nephrotoxicity and neurotoxicity thresholds are represented by horizontal dotted lines (red and black). (DOCX 13 kb)
228_2019_2761_Fig5_ESM.png (1001 kb)

(PNG 1001 kb)

228_2019_2761_MOESM2_ESM.tif (179 kb)
High resolution image (TIF 179 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Mélanie Rapp
    • 1
    • 2
    • 3
    Email author
  • Saïk Urien
    • 1
    • 2
  • Frantz Foissac
    • 1
    • 2
  • Agathe Béranger
    • 2
    • 3
  • Naïm Bouazza
    • 1
    • 2
  • Sihem Benaboud
    • 2
    • 4
  • Emmanuelle Bille
    • 5
  • Yi Zheng
    • 2
    • 3
  • Inès Gana
    • 2
    • 3
  • Florence Moulin
    • 3
  • Fabrice Lesage
    • 3
  • Sylvain Renolleau
    • 3
  • Jean Marc Tréluyer
    • 1
    • 2
    • 4
  • Déborah Hirt
    • 2
    • 4
  • Mehdi Oualha
    • 2
    • 3
  1. 1.Unité de recherche Clinique-Centre d’Investigation Clinique, Hôpital Cochin-NeckerUniversité Paris DescartesParisFrance
  2. 2.EA7323, Evaluation des thérapeutiques et pharmacologie périnatale et pédiatriqueUniversité Paris DescartesParisFrance
  3. 3.Service de réanimation et surveillance continue médico-chirurgicale, Hôpital Necker Enfants-MaladesUniversité Paris DescartesParisFrance
  4. 4.Service de pharmacologie clinique, Hôpital CochinUniversité Paris DescartesParisFrance
  5. 5.Laboratoire de microbiologie, Hôpital Necker Enfants-MaladesUniversité Paris DescartesParisFrance

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