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Parametric and Nonparametric Population Pharmacokinetic Models to Assess Probability of Target Attainment of Imipenem Concentrations in Critically Ill Patients
Population pharmacokinetic modeling and simulation (M&S) are used to improve antibiotic dosing. Little is known about the differences in parametric and nonparametric M&S. Our objectives were to compare (1) the external validation of parametric and nonparametric models of imipenem in critical...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8709176/ https://www.ncbi.nlm.nih.gov/pubmed/34959451 http://dx.doi.org/10.3390/pharmaceutics13122170 |
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author | de Velde, Femke de Winter, Brenda C. M. Neely, Michael N. Strojil, Jan Yamada, Walter M. Harbarth, Stephan Huttner, Angela van Gelder, Teun Koch, Birgit C. P. Muller, Anouk E. |
author_facet | de Velde, Femke de Winter, Brenda C. M. Neely, Michael N. Strojil, Jan Yamada, Walter M. Harbarth, Stephan Huttner, Angela van Gelder, Teun Koch, Birgit C. P. Muller, Anouk E. |
author_sort | de Velde, Femke |
collection | PubMed |
description | Population pharmacokinetic modeling and simulation (M&S) are used to improve antibiotic dosing. Little is known about the differences in parametric and nonparametric M&S. Our objectives were to compare (1) the external validation of parametric and nonparametric models of imipenem in critically ill patients and (2) the probability of target attainment (PTA) calculations using simulations of both models. The M&S software used was NONMEM 7.2 (parametric) and Pmetrics 1.5.2 (nonparametric). The external predictive performance of both models was adequate for eGFRs ≥ 78 mL/min but insufficient for lower eGFRs, indicating that the models (developed using a population with eGFR ≥ 60 mL/min) could not be extrapolated to lower eGFRs. Simulations were performed for three dosing regimens and three eGFRs (90, 120, 150 mL/min). Fifty percent of the PTA results were similar for both models, while for the other 50% the nonparametric model resulted in lower MICs. This was explained by a higher estimated between-subject variability of the nonparametric model. Simulations indicated that 1000 mg q6h is suitable to reach MICs of 2 mg/L for eGFRs of 90–120 mL/min. For MICs of 4 mg/L and for higher eGFRs, dosing recommendations are missing due to largely different PTA values per model. The consequences of the different modeling approaches in clinical practice should be further investigated. |
format | Online Article Text |
id | pubmed-8709176 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-87091762021-12-25 Parametric and Nonparametric Population Pharmacokinetic Models to Assess Probability of Target Attainment of Imipenem Concentrations in Critically Ill Patients de Velde, Femke de Winter, Brenda C. M. Neely, Michael N. Strojil, Jan Yamada, Walter M. Harbarth, Stephan Huttner, Angela van Gelder, Teun Koch, Birgit C. P. Muller, Anouk E. Pharmaceutics Article Population pharmacokinetic modeling and simulation (M&S) are used to improve antibiotic dosing. Little is known about the differences in parametric and nonparametric M&S. Our objectives were to compare (1) the external validation of parametric and nonparametric models of imipenem in critically ill patients and (2) the probability of target attainment (PTA) calculations using simulations of both models. The M&S software used was NONMEM 7.2 (parametric) and Pmetrics 1.5.2 (nonparametric). The external predictive performance of both models was adequate for eGFRs ≥ 78 mL/min but insufficient for lower eGFRs, indicating that the models (developed using a population with eGFR ≥ 60 mL/min) could not be extrapolated to lower eGFRs. Simulations were performed for three dosing regimens and three eGFRs (90, 120, 150 mL/min). Fifty percent of the PTA results were similar for both models, while for the other 50% the nonparametric model resulted in lower MICs. This was explained by a higher estimated between-subject variability of the nonparametric model. Simulations indicated that 1000 mg q6h is suitable to reach MICs of 2 mg/L for eGFRs of 90–120 mL/min. For MICs of 4 mg/L and for higher eGFRs, dosing recommendations are missing due to largely different PTA values per model. The consequences of the different modeling approaches in clinical practice should be further investigated. MDPI 2021-12-16 /pmc/articles/PMC8709176/ /pubmed/34959451 http://dx.doi.org/10.3390/pharmaceutics13122170 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article de Velde, Femke de Winter, Brenda C. M. Neely, Michael N. Strojil, Jan Yamada, Walter M. Harbarth, Stephan Huttner, Angela van Gelder, Teun Koch, Birgit C. P. Muller, Anouk E. Parametric and Nonparametric Population Pharmacokinetic Models to Assess Probability of Target Attainment of Imipenem Concentrations in Critically Ill Patients |
title | Parametric and Nonparametric Population Pharmacokinetic Models to Assess Probability of Target Attainment of Imipenem Concentrations in Critically Ill Patients |
title_full | Parametric and Nonparametric Population Pharmacokinetic Models to Assess Probability of Target Attainment of Imipenem Concentrations in Critically Ill Patients |
title_fullStr | Parametric and Nonparametric Population Pharmacokinetic Models to Assess Probability of Target Attainment of Imipenem Concentrations in Critically Ill Patients |
title_full_unstemmed | Parametric and Nonparametric Population Pharmacokinetic Models to Assess Probability of Target Attainment of Imipenem Concentrations in Critically Ill Patients |
title_short | Parametric and Nonparametric Population Pharmacokinetic Models to Assess Probability of Target Attainment of Imipenem Concentrations in Critically Ill Patients |
title_sort | parametric and nonparametric population pharmacokinetic models to assess probability of target attainment of imipenem concentrations in critically ill patients |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8709176/ https://www.ncbi.nlm.nih.gov/pubmed/34959451 http://dx.doi.org/10.3390/pharmaceutics13122170 |
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