Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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
_version_ 1784622870372024320
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
work_keys_str_mv AT develdefemke parametricandnonparametricpopulationpharmacokineticmodelstoassessprobabilityoftargetattainmentofimipenemconcentrationsincriticallyillpatients
AT dewinterbrendacm parametricandnonparametricpopulationpharmacokineticmodelstoassessprobabilityoftargetattainmentofimipenemconcentrationsincriticallyillpatients
AT neelymichaeln parametricandnonparametricpopulationpharmacokineticmodelstoassessprobabilityoftargetattainmentofimipenemconcentrationsincriticallyillpatients
AT strojiljan parametricandnonparametricpopulationpharmacokineticmodelstoassessprobabilityoftargetattainmentofimipenemconcentrationsincriticallyillpatients
AT yamadawalterm parametricandnonparametricpopulationpharmacokineticmodelstoassessprobabilityoftargetattainmentofimipenemconcentrationsincriticallyillpatients
AT harbarthstephan parametricandnonparametricpopulationpharmacokineticmodelstoassessprobabilityoftargetattainmentofimipenemconcentrationsincriticallyillpatients
AT huttnerangela parametricandnonparametricpopulationpharmacokineticmodelstoassessprobabilityoftargetattainmentofimipenemconcentrationsincriticallyillpatients
AT vangelderteun parametricandnonparametricpopulationpharmacokineticmodelstoassessprobabilityoftargetattainmentofimipenemconcentrationsincriticallyillpatients
AT kochbirgitcp parametricandnonparametricpopulationpharmacokineticmodelstoassessprobabilityoftargetattainmentofimipenemconcentrationsincriticallyillpatients
AT mulleranouke parametricandnonparametricpopulationpharmacokineticmodelstoassessprobabilityoftargetattainmentofimipenemconcentrationsincriticallyillpatients
AT parametricandnonparametricpopulationpharmacokineticmodelstoassessprobabilityoftargetattainmentofimipenemconcentrationsincriticallyillpatients