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Clinical Pharmacokinetics

, Volume 58, Issue 2, pp 223–233 | Cite as

Piperacillin Population Pharmacokinetics and Dosing Regimen Optimization in Critically Ill Children with Normal and Augmented Renal Clearance

  • Agathe BérangerEmail author
  • Sihem Benaboud
  • Saïk Urien
  • Florence Moulin
  • Emmanuelle Bille
  • Fabrice Lesage
  • Yi Zheng
  • Mathieu Genuini
  • Inès Gana
  • Sylvain Renolleau
  • Déborah Hirt
  • Jean-Marc Tréluyer
  • Mehdi Oualha
Original Research Article
  • 221 Downloads

Abstract

Background

Critically ill children frequently display observed alterations of pharmacokinetic (PK) parameters, leading to a reduction in β-lactam concentrations. This study aimed to develop a PK population model for piperacillin in order to optimize individual dosing regimens.

Methods

All children aged ≤ 18 years, weighing more than 2.5 kg, and receiving piperacillin infusions were included in this study. Piperacillin was quantified by high-performance liquid chromatography, and PK were described using the non-linear mixed-effect modeling software MONOLIX. Monte Carlo simulations were used to optimize dosing regimens in order to attain two PK targets: 50% fT>MIC and 100% fT>MIC.

Results

We included 50 children with a median (range) postnatal age of 2.3 years (0.1–18), body weight (BW) of 11.9 kg (2.7–50), Pediatric Logistic Organ Dysfunction-2 (PELOD-2) severity score of 4 (0–16), and estimated glomerular filtration rate (eGFR) of 142 mL.min−1.1.73 m−2 (29–675). A one-compartment model with first-order elimination adequately described the data. Median (range) values for piperacillin clearance (CL) and volume of distribution were 3 L.h−1 (0.71–10) and 0.33 L.kg−1 (0.21–0.86), respectively. BW was integrated with the allometric relationship. eGFR and PELOD-2 severity score were the covariates explaining between-subject variability in CL and volume, respectively. According to the simulations, extended and continuous infusion provided the highest probability of reaching the target of 50% fT>MIC and 100% fT>MIC for normal and augmented renal clearance, respectively.

Conclusions

Unlike standard intermittent piperacillin dosing regimens, extended and continuous infusion allows the PK targets to be reached, for children with normal or augmented renal clearance.

Trial Registration Number

Registered at http://www.clinicaltrials.gov (NCT02539407).

Notes

Acknowledgements

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. Agathe Béranger received a grant from the Agence Régionale de Santé Ile-de-France for a 1-year research fellowship in the EA7323.

Compliance with Ethical Standards

Conflict of interest

Agathe Béranger, Sihem Benaboud, Saïk Urien, Florence Moulin, Emmanuelle Bille, Fabrice Lesage, Yi Zheng, Mathieu Genuini, Inès Gana, Sylvain Renolleau, Déborah Hirt, Jean-Marc Tréluyer, and Mehdi Oualha declare no conflicts of interest.

Funding

The research study did not receive funds or support from any source.

Informed Consent

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

Supplementary material

40262_2018_682_MOESM1_ESM.tif (1.7 mb)
Probability of target attainment (100% fT>MIC in blue and 50% fT>MIC in green) according to our dosing regimen (DR), European (EMA) and American (FDA) assessments. (TIFF 1783 kb)
40262_2018_682_MOESM2_ESM.tiff (1.3 mb)
Probability of target attainment obtained from 1200 simulations for each body weight, for continuous infusion and a target defined as 100% fT>MIC. Four groups were defined according to renal function (a and c for augmented, and b and d for normal) and PELOD-2 severity score (a and b if < 5, and c and d if ≥ 5). Daily dosing regimens were defined according to renal function: 400 mg.kg−1.day−1 for augmented, 300 mg.kg−1.day−1 for normal. (TIFF 1341 kb)
40262_2018_682_MOESM3_ESM.tiff (1.5 mb)
Concentrations versus time courses for augmented renal clearance (eGFR > 130 mL.min−1.1.73 m−2), for PELOD-2 score < 5, depending on the different simulated administrations, for a daily dosing regimen of 400 mg.kg−1.day−1. The thick line depicts the median, the dashed lines are the 25th and 75th interquartile, and the dotted lines are the 95th confidence interval. The grey horizontal lines are the inferior (16 mg.L−1) and superior (150 mg.L−1) concentration targets, respectively. (TIFF 1565 kb)
40262_2018_682_MOESM4_ESM.tiff (1.5 mb)
Concentrations versus time courses for normal renal function (eGFR 40-130 mL.min−1.1.73 m−2), for PELOD-2 score < 5, depending on the different simulated administrations, for a daily dosing regimen of 300 mg.kg−1.day−1. The thick line depicts the median, the dashed lines are the 25th and 75th interquartile, and the dotted lines are the 95th confidence interval. The grey horizontal lines are the inferior (16 mg.L−1) and superior (150 mg.L−1) concentrations target, respectively. (TIFF 1565 kb)

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Agathe Béranger
    • 1
    • 2
    Email author
  • Sihem Benaboud
    • 2
    • 3
  • Saïk Urien
    • 1
    • 2
  • Florence Moulin
    • 4
  • Emmanuelle Bille
    • 5
  • Fabrice Lesage
    • 4
  • Yi Zheng
    • 3
  • Mathieu Genuini
    • 4
  • Inès Gana
    • 3
  • Sylvain Renolleau
    • 4
  • Déborah Hirt
    • 2
    • 3
  • Jean-Marc Tréluyer
    • 1
    • 2
    • 3
  • Mehdi Oualha
    • 2
    • 4
  1. 1.Unité de Recherche Clinique-Centre d’Investigation CliniqueHôpital Cochin-Necker, Université Paris Descartes, Sorbonne-Paris CitéParisFrance
  2. 2.EA7323, Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, Université Paris DescartesParisFrance
  3. 3.Service de pharmacologie cliniqueHôpital Cochin, Université Paris Descartes, Sorbonne-Paris CitéParisFrance
  4. 4.Service de réanimation et surveillance continue médico-chirurgicalesHôpital Necker Enfants-Malades, Université Paris Descartes, Sorbonne-Paris CitéParisFrance
  5. 5.Laboratoire de microbiologieHôpital Necker Enfants-Malades, Université Paris Descartes, Sorbonne-Paris CitéParisFrance

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