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Using a Validated Population Pharmacokinetic Model for Dosing Recommendations of Continuous Infusion Piperacillin for Critically Ill Adult Patients

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Abstract

Background and Objective

Piperacillin is a broad-spectrum β-lactam antibiotic commonly prescribed in intensive care units. Many piperacillin population pharmacokinetic models have been published, but few underwent an external evaluation. External evaluation is an important process to determine a model’s capability of being generalized to other hospitals. We aimed to assess the predictive performance of these models with an external validation dataset.

Methods

Six models were evaluated with a dataset consisting of 30 critically ill patients (35 samples) receiving piperacillin by continuous infusion. Models were subject to prediction-based (bias and imprecision) and simulation-based evaluations. When a model had an acceptable evaluation, it was used for dosing simulations to evaluate the probability of target attainment.

Results

Bias and imprecision ranged from − 35.7 to 295% and from 22.7 to 295%, respectively. The models of Klastrup et al. and of Udy et al. were acceptable according to our criteria and were used for dosing simulations. Simulations showed that a loading dose of 4 g followed by a maintenance dose of 16 g/24 h of piperacillin infused continuously was necessary to remain above a pharmacokinetic-pharmacodynamic target set as a minimal inhibitory concentration of 16 mg/L in 90% of patients, for a median patient with a creatinine clearance of 76 mL/min.

Conclusions

Despite the considerable variation in the predictive performance of the models with the external validation dataset, this study was able to validate two of these models and led to the elaboration of a dosing nomogram for piperacillin by continuous infusion that can be used by clinicians in intensive care units.

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Authors and Affiliations

  1. Faculty of Pharmacy, Université de Montréal, Pavillon Jean-Coutu, 2940 Chemin de Polytechnique, Montréal, QC, H3T 1J4, Canada

    Ibrahim El-Haffaf & Amélie Marsot

  2. Laboratoire de Suivi Thérapeutique Pharmacologique et Pharmacocinétique, Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada

    Ibrahim El-Haffaf & Amélie Marsot

  3. Service de Pharmacologie Clinique et Pharmacovigilance, Assistance Publique des Hôpitaux de Marseille, Aix Marseille Université, Institut de Neurosciences des Systèmes, Inserm UMR 1106, Marseille, France

    Romain Guilhaumou

  4. Service d’Anesthésie-Réanimation, Hôpital de la Timone, Assistance Publique des Hôpitaux de Marseille et Institut de Neurosciences de la Timone, CNRS, Aix Marseille Université, Marseille, France

    Lionel Velly

  5. Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada

    Amélie Marsot

Authors
  1. Ibrahim El-Haffaf
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  2. Romain Guilhaumou
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  3. Lionel Velly
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  4. Amélie Marsot
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Corresponding author

Correspondence to Ibrahim El-Haffaf.

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Funding

No funding was received for the preparation of this article.

Conflict of interest

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

Ethics approval

Ethical approval was granted by the local Ethics Committee of Aix Marseille Université (no. 2016-28-09-04).

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Not applicable.

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Not applicable.

Availability of data and material

Data related to the evaluated models weres collected from the already published articles in the literature. Patient data obtained from the Hôpital de la Timone are not publicly available.

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Author contribution

IE evaluated the models, analyzed the data, and wrote the manuscript. RG, LV, and AM validated the manuscript. AM supervised the work.

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El-Haffaf, I., Guilhaumou, R., Velly, L. et al. Using a Validated Population Pharmacokinetic Model for Dosing Recommendations of Continuous Infusion Piperacillin for Critically Ill Adult Patients. Clin Pharmacokinet 61, 895–906 (2022). https://doi.org/10.1007/s40262-022-01118-1

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