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Meropenem Population Pharmacokinetics and Dosing Regimen Optimization in Critically Ill Children Receiving Continuous Renal Replacement Therapy

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Abstract

Background and Objective

We aimed to develop a meropenem population pharmacokinetic model in critically ill children receiving continuous renal replacement therapy and simulate dosing regimens to optimize patient exposure.

Methods

Meropenem plasma concentration was quantified by high-performance liquid chromatography. Meropenem pharmacokinetics was investigated using a non-linear mixed-effect modeling approach. Monte Carlo simulations were performed to compute the optimal scheme of administration, according to the target of a 100% inter-dose interval time in which concentration is one to four times above the minimum inhibitory concentration (100% fT>1–4×MIC).

Results

A total of 27 patients with a median age of 4 [interquartile range 0–11] years, a median body weight of 16 [range 7–35] kg receiving continuous renal replacement therapy were included. Concentration–time courses were best described by a one-compartment model with first-order elimination. Body weight (BW) produced significant effects on volume of distribution (V) and BW and continuous renal replacement therapy effluent flow rate (Qeff) produced significant effects on clearance (CL): \({V}_{i}={V}_{pop }{x (\frac{BWi}{70})}^{1}\) and \({CL}_{i}={CL}_{pop }x ({\frac{BWi}{70})}^{0.75} x ({\frac{Qeffi}{1200})}^{0.337}\), where Vpop and CLpop estimates were 32.5 L and 5.88 L/h, respectively, normalized to a 70-kg BW and median Qeff at 1200 mL/h. Using this final model and Monte Carlo simulations, for patients with Qeff over 1200 mL/h, meropenem continuous infusion was adequate in most cases to attain 100% fT>1–4xMIC. For bacterial infections with a low minimum inhibitory concentration (≤2 mg/L), meropenem intermitent administration was appropriate for patients weighing more than 20 kg with Qeff <500 mL/h and for patients weighing more than 10 kg with Qeff <100 mL/h.

Conclusions

Meropenem exposure in critically ill children receiving continuous renal replacement therapy needs dosing adjustments to the minimum inhibitory concentration that take into account body weight and the continuous renal replacement therapy effluent flow rate.

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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.

Author information

Authors and Affiliations

  1. Service de Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, AP-HP, Université Paris Cité, 75018, Paris, France

    Michael Thy

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

    Michael Thy, Naim Bouazza, Frantz Foissac, Agathe Béranger, Jean-Marc Tréluyer, Sihem Benaboud & Mehdi Oualha

  3. Unité de Recherche Clinique-Centre d’Investigation Clinique, Hôpital Cochin-Necker, AP-HP, Université Paris Cité, Paris, France

    Saik Urien, Naim Bouazza, Frantz Foissac & Inès Gana

  4. Service deMmicrobiologieHôpital Necker Enfants-Malades, AP-HP, Université Paris Cité, Paris, France

    Emmanuelle Bille & Jean-Marc Tréluyer

  5. Service de Pharmacologie Clinique, Hôpital Cochin, AP-HP, Université Paris Cité, Paris, France

    Jean-Marc Tréluyer & Sihem Benaboud

  6. Service de Réanimation Chirurgicale Cardiaque Pédiatrique, Hôpital Necker Enfants-Malades, AP-HP, Université de Paris Cité, Paris, France

    Agathe Béranger

  7. Service de Pédiatrie Générale et Infectieuse, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, AP-HP, Université Paris Cité, Paris, France

    Julie Toubiana

  8. Service de Néphrologie Pédiatrique, Centre de Référence MARHEA, Hôpital Necker-Enfants Malades, AP-HP, Université Paris Cité, Paris, France

    Romain Berthaud

  9. Service de Réanimation et Surveillance Continue Médicochirurgicales, Hôpital Necker Enfants-Malades, AP-HP, Université Paris Cité, Paris, France

    Fabrice Lesage, Sylvain Renolleau & Mehdi Oualha

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  1. Michael Thy
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Corresponding author

Correspondence to Michael Thy.

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Authors’ contributions

MT collected the data and drafted the manuscript. MT and MO conceived the study and critically revised the manuscript. EB identified pathogen agents and related MIC and also critically revised the manuscript. MT, SU, FF, and NB contributed to the acquisition, analysis, and interpretation of data and also critically revised the manuscript. IG, AB, JT, RB, FL, SR, JMT, and SB critically revised the manuscript.

Funding

Michael Thy received a grant from the “Société de Reanimation de Langue Française” supporting research on this topic.

Conflicts of Interest

The authors have no conflicts of interest that are directly relevant to the content of this article.

Ethics Approval

The Ethics Committee of Necker Hospital approved the study, which was registered at www.clinicaltrials.gov (NCT02539407).

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Before any inclusion, written consent was obtained from children’s parent(s).

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Not applicable.

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All data generated or analyzed during this study are included in this study or its supplementary material files. Further inquiries can be directed to the corresponding author.

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Thy, M., Urien, S., Bouazza, N. et al. Meropenem Population Pharmacokinetics and Dosing Regimen Optimization in Critically Ill Children Receiving Continuous Renal Replacement Therapy. Clin Pharmacokinet 61, 1609–1621 (2022). https://doi.org/10.1007/s40262-022-01179-2

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