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

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

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 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.

Conclusion

Continuous infusion allows reaching the fT > MIC targets safely in children with normal or increased renal clearance.

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Abbreviations

ARC:

Augmented renal clearance

BIC:

Bayesian information criteria

BSV:

Between-subject variability

BW:

Body weight

CL:

Clearance

CRP:

C-reactive protein

CRRT:

Continuous renal replacement therapy

ECMO:

Extracorporeal membrane oxygenation

EMA:

European Medicines Agency

eGFR:

Estimated glomerular filtration rate

MIC:

Minimum inhibitory concentration

PCT:

Procalcitonin

PICU:

Pediatric intensive care unit

PK:

Pharmacokinetics

PTA:

Probability of target attainment

V :

Volume of distribution

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Acknowledgments

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

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.”

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Authors and Affiliations

  1. Unité de recherche Clinique-Centre d’Investigation Clinique, Hôpital Cochin-Necker, Université Paris Descartes, Sorbonne-Paris Cité, 149 rue de Sèvres, 75015, Paris, France

    Mélanie Rapp, Saïk Urien, Frantz Foissac, Naïm Bouazza & Jean Marc Tréluyer

  2. EA7323, Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, Université Paris Descartes, 27 rue du Faubourg Saint Jacques, 75014, Paris, France

    Mélanie Rapp, Saïk Urien, Frantz Foissac, Agathe Béranger, Naïm Bouazza, Sihem Benaboud, Yi Zheng, Inès Gana, Jean Marc Tréluyer, Déborah Hirt & Mehdi Oualha

  3. Service de réanimation et surveillance continue médico-chirurgicale, Hôpital Necker Enfants-Malades, Université Paris Descartes, Sorbonne-Paris Cité, 149 rue de Sèvres, 75015, Paris, France

    Mélanie Rapp, Agathe Béranger, Yi Zheng, Inès Gana, Florence Moulin, Fabrice Lesage, Sylvain Renolleau & Mehdi Oualha

  4. Service de pharmacologie clinique, Hôpital Cochin, Université Paris Descartes, Sorbonne-Paris Cité, 27 rue du Faubourg Saint Jacques, 75014, Paris, France

    Sihem Benaboud, Jean Marc Tréluyer & Déborah Hirt

  5. Laboratoire de microbiologie, Hôpital Necker Enfants-Malades, Université Paris Descartes, Sorbonne-Paris Cité, 149 rue de Sèvres, 75015, Paris, France

    Emmanuelle Bille

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  1. Mélanie Rapp
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Corresponding author

Correspondence to Mélanie Rapp.

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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).

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The authors declare that they have no conflict of interest.

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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)

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Rapp, M., Urien, S., Foissac, F. et al. Population pharmacokinetics of meropenem in critically ill children with different renal functions. Eur J Clin Pharmacol 76, 61–71 (2020). https://doi.org/10.1007/s00228-019-02761-7

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