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Daptomycin Population Pharmacokinetics in Patients Affected by Severe Gram-Positive Infections: An Update

Daptomycin pharmacokinetics may not depend on renal function only and it significantly differs between healthy volunteers and severely ill patients. Herein, we propose a population pharmacokinetics model based on 424 plasma daptomycin concentrations collected from 156 patients affected by severe Gra...

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Autores principales: Balice, Giuseppe, Passino, Claudio, Bongiorni, Maria Grazia, Segreti, Luca, Russo, Alessandro, Lastella, Marianna, Luci, Giacomo, Falcone, Marco, Di Paolo, Antonello
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311615/
https://www.ncbi.nlm.nih.gov/pubmed/35884168
http://dx.doi.org/10.3390/antibiotics11070914
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author Balice, Giuseppe
Passino, Claudio
Bongiorni, Maria Grazia
Segreti, Luca
Russo, Alessandro
Lastella, Marianna
Luci, Giacomo
Falcone, Marco
Di Paolo, Antonello
author_facet Balice, Giuseppe
Passino, Claudio
Bongiorni, Maria Grazia
Segreti, Luca
Russo, Alessandro
Lastella, Marianna
Luci, Giacomo
Falcone, Marco
Di Paolo, Antonello
author_sort Balice, Giuseppe
collection PubMed
description Daptomycin pharmacokinetics may not depend on renal function only and it significantly differs between healthy volunteers and severely ill patients. Herein, we propose a population pharmacokinetics model based on 424 plasma daptomycin concentrations collected from 156 patients affected by severe Gram-positive infections during a routine therapeutic drug monitoring protocol. Model building and validation were performed using NONMEM 7.2 (ICON plc), Xpose4 and Perl-speaks-to-NONMEM. The final pop-PK model was a one-compartment first-order elimination model, with a 2.7% IIV for drug clearance (Cl), influence of creatinine clearance on drug clearance and of sex on distribution volume. After model validation, we simulated 10,000 patients with the Monte-Carlo method to predict the efficacy and tolerability of different daptomycin daily dosages. For the most common 6 mg/kg daily dose, the simulated probability of overcoming the toxic minimum concentration (24.3 mg/L) was 14.8% and the efficacy (expressed as a cumulative fraction of response) against methicillin-resistant S. aureus, S. pneumoniae and E. faecium was 95.77%, 99.99% and 68%, respectively. According to the model-informed precision dosing paradigm, pharmacokinetic models such as ours could help clinicians to perform patient-tailored antimicrobial dosing and maximize the odds of therapy success without neglecting toxicity risks.
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spelling pubmed-93116152022-07-26 Daptomycin Population Pharmacokinetics in Patients Affected by Severe Gram-Positive Infections: An Update Balice, Giuseppe Passino, Claudio Bongiorni, Maria Grazia Segreti, Luca Russo, Alessandro Lastella, Marianna Luci, Giacomo Falcone, Marco Di Paolo, Antonello Antibiotics (Basel) Article Daptomycin pharmacokinetics may not depend on renal function only and it significantly differs between healthy volunteers and severely ill patients. Herein, we propose a population pharmacokinetics model based on 424 plasma daptomycin concentrations collected from 156 patients affected by severe Gram-positive infections during a routine therapeutic drug monitoring protocol. Model building and validation were performed using NONMEM 7.2 (ICON plc), Xpose4 and Perl-speaks-to-NONMEM. The final pop-PK model was a one-compartment first-order elimination model, with a 2.7% IIV for drug clearance (Cl), influence of creatinine clearance on drug clearance and of sex on distribution volume. After model validation, we simulated 10,000 patients with the Monte-Carlo method to predict the efficacy and tolerability of different daptomycin daily dosages. For the most common 6 mg/kg daily dose, the simulated probability of overcoming the toxic minimum concentration (24.3 mg/L) was 14.8% and the efficacy (expressed as a cumulative fraction of response) against methicillin-resistant S. aureus, S. pneumoniae and E. faecium was 95.77%, 99.99% and 68%, respectively. According to the model-informed precision dosing paradigm, pharmacokinetic models such as ours could help clinicians to perform patient-tailored antimicrobial dosing and maximize the odds of therapy success without neglecting toxicity risks. MDPI 2022-07-07 /pmc/articles/PMC9311615/ /pubmed/35884168 http://dx.doi.org/10.3390/antibiotics11070914 Text en © 2022 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
Balice, Giuseppe
Passino, Claudio
Bongiorni, Maria Grazia
Segreti, Luca
Russo, Alessandro
Lastella, Marianna
Luci, Giacomo
Falcone, Marco
Di Paolo, Antonello
Daptomycin Population Pharmacokinetics in Patients Affected by Severe Gram-Positive Infections: An Update
title Daptomycin Population Pharmacokinetics in Patients Affected by Severe Gram-Positive Infections: An Update
title_full Daptomycin Population Pharmacokinetics in Patients Affected by Severe Gram-Positive Infections: An Update
title_fullStr Daptomycin Population Pharmacokinetics in Patients Affected by Severe Gram-Positive Infections: An Update
title_full_unstemmed Daptomycin Population Pharmacokinetics in Patients Affected by Severe Gram-Positive Infections: An Update
title_short Daptomycin Population Pharmacokinetics in Patients Affected by Severe Gram-Positive Infections: An Update
title_sort daptomycin population pharmacokinetics in patients affected by severe gram-positive infections: an update
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311615/
https://www.ncbi.nlm.nih.gov/pubmed/35884168
http://dx.doi.org/10.3390/antibiotics11070914
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