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Towards model-informed precision dosing of piperacillin: multicenter systematic external evaluation of pharmacokinetic models in critically ill adults with a focus on Bayesian forecasting

PURPOSE: Inadequate piperacillin (PIP) exposure in intensive care unit (ICU) patients threatens therapeutic success. Model-informed precision dosing (MIPD) might be promising to individualize dosing; however, the transferability of published models to external populations is uncertain. This study ai...

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Autores principales: Greppmair, Sebastian, Brinkmann, Alexander, Roehr, Anka, Frey, Otto, Hagel, Stefan, Dorn, Christoph, Marsot, Amélie, El-Haffaf, Ibrahim, Zoller, Michael, Saller, Thomas, Zander, Johannes, Schatz, Lea Marie, Scharf, Christina, Briegel, Josef, Minichmayr, Iris K., Wicha, Sebastian G., Liebchen, Uwe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10425489/
https://www.ncbi.nlm.nih.gov/pubmed/37439872
http://dx.doi.org/10.1007/s00134-023-07154-0
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author Greppmair, Sebastian
Brinkmann, Alexander
Roehr, Anka
Frey, Otto
Hagel, Stefan
Dorn, Christoph
Marsot, Amélie
El-Haffaf, Ibrahim
Zoller, Michael
Saller, Thomas
Zander, Johannes
Schatz, Lea Marie
Scharf, Christina
Briegel, Josef
Minichmayr, Iris K.
Wicha, Sebastian G.
Liebchen, Uwe
author_facet Greppmair, Sebastian
Brinkmann, Alexander
Roehr, Anka
Frey, Otto
Hagel, Stefan
Dorn, Christoph
Marsot, Amélie
El-Haffaf, Ibrahim
Zoller, Michael
Saller, Thomas
Zander, Johannes
Schatz, Lea Marie
Scharf, Christina
Briegel, Josef
Minichmayr, Iris K.
Wicha, Sebastian G.
Liebchen, Uwe
author_sort Greppmair, Sebastian
collection PubMed
description PURPOSE: Inadequate piperacillin (PIP) exposure in intensive care unit (ICU) patients threatens therapeutic success. Model-informed precision dosing (MIPD) might be promising to individualize dosing; however, the transferability of published models to external populations is uncertain. This study aimed to externally evaluate the available PIP population pharmacokinetic (PopPK) models. METHODS: A multicenter dataset of 561 ICU patients (11 centers/3654 concentrations) was used for the evaluation of 24 identified models. Model performance was investigated for a priori (A) predictions, i.e., considering dosing records and patient characteristics only, and for Bayesian forecasting, i.e., additionally including the first (B1) or first and second (B2) therapeutic drug monitoring (TDM) samples per patient. Median relative prediction error (MPE) [%] and median absolute relative prediction error (MAPE) [%] were calculated to quantify accuracy and precision. RESULTS: The evaluation revealed a large inter-model variability (A: MPE − 135.6–78.3% and MAPE 35.7–135.6%). Integration of TDM data improved all model predictions (B1/B2 relative improvement vs. A: |MPE|(median_all_models) 45.1/67.5%; MAPE(median_all_models) 29/39%). The model by Kim et al. was identified to be most appropriate for the total dataset (A/B1/B2: MPE − 9.8/− 5.9/− 0.9%; MAPE 37/27.3/23.7%), Udy et al. performed best in patients receiving intermittent infusion, and Klastrup et al. best predicted patients receiving continuous infusion. Additional evaluations stratified by sex and renal replacement therapy revealed further promising models. CONCLUSION: The predictive performance of published PIP models in ICU patients varied considerably, highlighting the relevance of appropriate model selection for MIPD. Our differentiated external evaluation identified specific models suitable for clinical use, especially in combination with TDM. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00134-023-07154-0.
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spelling pubmed-104254892023-08-16 Towards model-informed precision dosing of piperacillin: multicenter systematic external evaluation of pharmacokinetic models in critically ill adults with a focus on Bayesian forecasting Greppmair, Sebastian Brinkmann, Alexander Roehr, Anka Frey, Otto Hagel, Stefan Dorn, Christoph Marsot, Amélie El-Haffaf, Ibrahim Zoller, Michael Saller, Thomas Zander, Johannes Schatz, Lea Marie Scharf, Christina Briegel, Josef Minichmayr, Iris K. Wicha, Sebastian G. Liebchen, Uwe Intensive Care Med Original PURPOSE: Inadequate piperacillin (PIP) exposure in intensive care unit (ICU) patients threatens therapeutic success. Model-informed precision dosing (MIPD) might be promising to individualize dosing; however, the transferability of published models to external populations is uncertain. This study aimed to externally evaluate the available PIP population pharmacokinetic (PopPK) models. METHODS: A multicenter dataset of 561 ICU patients (11 centers/3654 concentrations) was used for the evaluation of 24 identified models. Model performance was investigated for a priori (A) predictions, i.e., considering dosing records and patient characteristics only, and for Bayesian forecasting, i.e., additionally including the first (B1) or first and second (B2) therapeutic drug monitoring (TDM) samples per patient. Median relative prediction error (MPE) [%] and median absolute relative prediction error (MAPE) [%] were calculated to quantify accuracy and precision. RESULTS: The evaluation revealed a large inter-model variability (A: MPE − 135.6–78.3% and MAPE 35.7–135.6%). Integration of TDM data improved all model predictions (B1/B2 relative improvement vs. A: |MPE|(median_all_models) 45.1/67.5%; MAPE(median_all_models) 29/39%). The model by Kim et al. was identified to be most appropriate for the total dataset (A/B1/B2: MPE − 9.8/− 5.9/− 0.9%; MAPE 37/27.3/23.7%), Udy et al. performed best in patients receiving intermittent infusion, and Klastrup et al. best predicted patients receiving continuous infusion. Additional evaluations stratified by sex and renal replacement therapy revealed further promising models. CONCLUSION: The predictive performance of published PIP models in ICU patients varied considerably, highlighting the relevance of appropriate model selection for MIPD. Our differentiated external evaluation identified specific models suitable for clinical use, especially in combination with TDM. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00134-023-07154-0. Springer Berlin Heidelberg 2023-07-13 2023 /pmc/articles/PMC10425489/ /pubmed/37439872 http://dx.doi.org/10.1007/s00134-023-07154-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by-nc/4.0/Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Original
Greppmair, Sebastian
Brinkmann, Alexander
Roehr, Anka
Frey, Otto
Hagel, Stefan
Dorn, Christoph
Marsot, Amélie
El-Haffaf, Ibrahim
Zoller, Michael
Saller, Thomas
Zander, Johannes
Schatz, Lea Marie
Scharf, Christina
Briegel, Josef
Minichmayr, Iris K.
Wicha, Sebastian G.
Liebchen, Uwe
Towards model-informed precision dosing of piperacillin: multicenter systematic external evaluation of pharmacokinetic models in critically ill adults with a focus on Bayesian forecasting
title Towards model-informed precision dosing of piperacillin: multicenter systematic external evaluation of pharmacokinetic models in critically ill adults with a focus on Bayesian forecasting
title_full Towards model-informed precision dosing of piperacillin: multicenter systematic external evaluation of pharmacokinetic models in critically ill adults with a focus on Bayesian forecasting
title_fullStr Towards model-informed precision dosing of piperacillin: multicenter systematic external evaluation of pharmacokinetic models in critically ill adults with a focus on Bayesian forecasting
title_full_unstemmed Towards model-informed precision dosing of piperacillin: multicenter systematic external evaluation of pharmacokinetic models in critically ill adults with a focus on Bayesian forecasting
title_short Towards model-informed precision dosing of piperacillin: multicenter systematic external evaluation of pharmacokinetic models in critically ill adults with a focus on Bayesian forecasting
title_sort towards model-informed precision dosing of piperacillin: multicenter systematic external evaluation of pharmacokinetic models in critically ill adults with a focus on bayesian forecasting
topic Original
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10425489/
https://www.ncbi.nlm.nih.gov/pubmed/37439872
http://dx.doi.org/10.1007/s00134-023-07154-0
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