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Piperacillin Population Pharmacokinetics and Dosing Regimen Optimization in Critically Ill Children with Normal and
Agathe Béranger1,2, Sihem Benaboud3,4, Saïk Urien5,3
1Unité de Recherche Clinique-Centre d'Investigation Clinique, Hôpital Cochin-Necker, Université Paris Descartes, Sorbonne-Paris Cité, 149 rue de Sèvres, 75015, Paris, France. agathe.beranger@aphp.fr.
Insights
Optimizing piperacillin dosing in critically ill children is crucial. Extended or continuous infusions, unlike standard intermittent regimens, improve the likelihood of reaching therapeutic pharmacokinetic targets in pediatric patients.
Area of Science:
- Pediatric pharmacology
- Critical care medicine
- Pharmacokinetics
Background:
- Critically ill children often exhibit altered pharmacokinetic (PK) parameters, leading to reduced beta-lactam concentrations.
- Optimizing piperacillin dosing is essential for effective treatment in this population.
Purpose of the Study:
- To develop a population pharmacokinetic (PK) model for piperacillin in pediatric patients.
- To optimize individual dosing regimens for piperacillin in critically ill children.
Main Methods:
- A population PK model was developed using non-linear mixed-effect modeling (MONOLIX) software.
- Piperacillin concentrations were quantified using high-performance liquid chromatography.
- Monte Carlo simulations were performed to optimize dosing strategies for achieving specific PK targets (50% and 100% fT>MIC).
Main Results:
- A one-compartment model with first-order elimination adequately described piperacillin PK.
- Body weight, estimated glomerular filtration rate (eGFR), and Pediatric Logistic Organ Dysfunction-2 (PELOD-2) score were identified as significant covariates.
- Simulations indicated that extended and continuous infusions were superior for achieving therapeutic targets across different renal clearance levels.
Conclusions:
- Extended and continuous piperacillin infusions are more effective than intermittent dosing for achieving PK targets in children.
- These optimized infusion strategies are beneficial for both normal and augmented renal clearance in pediatric patients.
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).
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