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Population Pharmacokinetic Model to Optimize Cefotaxime Dosing Regimen in Critically Ill Children

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Abstract

Background

During sepsis, optimal plasma antibiotic concentrations are mandatory. Modifications of pharmacokinetic parameters could lead to low drug concentrations and therefore, insufficient therapeutic levels.

Objective

The aim of this study was to build a population pharmacokinetic model for cefotaxime and its metabolite desacetylcefotaxime in order to optimize individual dosing regimens for critically ill children.

Methods

All children aged < 18 years, weighing more than 2.5 kg, and receiving intermittent cefotaxime infusions were included in this study. Cefotaxime and desacetylcefotaxime were quantified by high-performance liquid chromatography. Pharmacokinetics were described using the non-linear mixed-effect modeling software MONOLIX, and Monte Carlo simulations were used to optimize dosing regimen in order to maintain serum concentrations above the target concentration (defined at 2 mg·L−1) throughout the dosing interval.

Results

We included 49 children with a median (range) postnatal age of 23.7 (0.2–229) months, and median body weight (range) of 10.9 (2.5–68) kg. A one-compartment model with first-order elimination adequately described the data. Median (range) values for cefotaxime clearance, desacetylcefotaxime clearance, and volume of distribution were 0.97 (0.3–7.1) L·h−1, 3.2 (0.6–16.3) L·h−1, and 0.3 (0.2–0.41) L·kg−1, respectively. Body weight and postnatal age were statistically significant covariates. Cefotaxime-calculated residual concentrations were low, and no patient succeeded in attaining the target. Unlike intermittent administration, a dosing regimen of 100 mg·kg−1·day−1 administered by continuous infusion provided a probability of target attainment of 100%, regardless of age and weight.

Conclusions

Standard intermittent cefotaxime dosing regimens in critically ill children are not adequate to reach the target. We showed that, for the same daily dose, continuous infusion was the only administration that enabled the target to be attained, for children over 1 month of age. As continuous administration is achievable in the pediatric intensive care unit, it should be considered for clinical practice.

Trial registration number

Registered at http://www.clinicaltrials.gov, NCT02539407.

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Acknowledgements

The authors thank the PICU team (physicians and nurses) who included the children and realized the samples, making this work possible. They also thank the Pharmacology Laboratory of the Cochin Teaching Hospital, which analyzed the samples. Agathe Béranger is currently receiving a grant from the Agence Régionale de Santé Ile-de-France, for 1 year of research, as a fellow in the EA7323.

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Authors and Affiliations

  1. Unité de Recherche Clinique, Hôpital Cochin-Necker, Université Paris Descartes, Sorbonne-Paris Cité, Paris, France

    Agathe Béranger, Saïk Urien & Jean-Marc Tréluyer

  2. EA7323, Evaluation des Thérapeutiques et Pharmacologie Périnatale et Pédiatrique, Université Paris Descartes, Paris, France

    Agathe Béranger, Mehdi Oualha, Saïk Urien, Radia Aboura, Déborah Hirt, Jean-Marc Tréluyer & Sihem Benaboud

  3. Service de Réanimation et Surveillance Continue Médico-Chirurgicales, Hôpital Necker Enfants-Malades, Université Paris Descartes, Sorbonne-Paris Cité, 149 rue de Sèvres, 75015, Paris, France

    Mehdi Oualha, Mathieu Genuini, Sylvain Renolleau & Claire Heilbronner

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

    Radia Aboura, Déborah Hirt, Jean-Marc Tréluyer & Sihem Benaboud

  5. Service de Pédiatrie Générale, Equipe Mobile D’Infectiologie, Hôpital Necker-Enfants Malades, Université Paris Descartes, Sorbonne-Paris Cité, 149 rue de Sèvres, 75015, Paris, France

    Julie Toubiana

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  1. Agathe Béranger
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Corresponding author

Correspondence to Agathe Béranger.

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Conflicts of interest

Agathe Béranger, Mehdi Oualha, Saïk Urien, Mathieu Genuini, Sylvain Renolleau, Radia Aboura, Déborah Hirt, Claire Heilbronner, Julie Toubiana, Jean-Marc Tréluyer, and Sihem Benaboud declare no conflicts of interest.

Funding

This research study did not receive funds or support from any sources.

Informed consent

Informed consent was obtained from all parents of the children included in the study.

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Supplementary material 1 (DOCX 13 kb)

40262_2017_602_MOESM2_ESM.tif

Supplementary Fig. 1 Description of the pharmacokinetic model. IV 30 min shows the intravenous infusion over 30 min of the CTX. VCTX and VD-CTX are the volume of distribution for the parent and the metabolite respectively. CL10 and CL20 are the elimination clearance for the parent and the metabolite respectively. CL12 is the metabolite formation clearance. (TIFF 201 kb)

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Béranger, A., Oualha, M., Urien, S. et al. Population Pharmacokinetic Model to Optimize Cefotaxime Dosing Regimen in Critically Ill Children. Clin Pharmacokinet 57, 867–875 (2018). https://doi.org/10.1007/s40262-017-0602-9

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  • DOI: https://doi.org/10.1007/s40262-017-0602-9

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