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Physiologically-Based Pharmacokinetic Modelling to Predict the Pharmacokinetics and Pharmacodynamics of Linezolid in Adults and Children with Tuberculous Meningitis
Linezolid is used off-label for treatment of central nervous system infections. However, its pharmacokinetics and target attainment in cranial cerebrospinal fluid (CSF) in tuberculous meningitis patients is unknown. This study aimed to predict linezolid cranial CSF concentrations and assess attainme...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10135070/ https://www.ncbi.nlm.nih.gov/pubmed/37107064 http://dx.doi.org/10.3390/antibiotics12040702 |
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author | Litjens, Carlijn H. C. Verscheijden, Laurens F. M. Svensson, Elin M. van den Broek, Petra H. H. van Hove, Hedwig Koenderink, Jan B. Russel, Frans G. M. Aarnoutse, Rob E. te Brake, Lindsey H. M. |
author_facet | Litjens, Carlijn H. C. Verscheijden, Laurens F. M. Svensson, Elin M. van den Broek, Petra H. H. van Hove, Hedwig Koenderink, Jan B. Russel, Frans G. M. Aarnoutse, Rob E. te Brake, Lindsey H. M. |
author_sort | Litjens, Carlijn H. C. |
collection | PubMed |
description | Linezolid is used off-label for treatment of central nervous system infections. However, its pharmacokinetics and target attainment in cranial cerebrospinal fluid (CSF) in tuberculous meningitis patients is unknown. This study aimed to predict linezolid cranial CSF concentrations and assess attainment of pharmacodynamic (PD) thresholds (AUC:MIC of >119) in plasma and cranial CSF of adults and children with tuberculous meningitis. A physiologically based pharmacokinetic (PBPK) model was developed to predict linezolid cranial CSF profiles based on reported plasma concentrations. Simulated steady-state PK curves in plasma and cranial CSF after linezolid doses of 300 mg BID, 600 mg BID, and 1200 mg QD in adults resulted in geometric mean AUC:MIC ratios in plasma of 118, 281, and 262 and mean cranial CSF AUC:MIC ratios of 74, 181, and 166, respectively. In children using ~10 mg/kg BID linezolid, AUC:MIC values at steady-state in plasma and cranial CSF were 202 and 135, respectively. Our model predicts that 1200 mg per day in adults, either 600 mg BID or 1200 mg QD, results in reasonable (87%) target attainment in cranial CSF. Target attainment in our simulated paediatric population was moderate (56% in cranial CSF). Our PBPK model can support linezolid dose optimization efforts by simulating target attainment close to the site of TBM disease. |
format | Online Article Text |
id | pubmed-10135070 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-101350702023-04-28 Physiologically-Based Pharmacokinetic Modelling to Predict the Pharmacokinetics and Pharmacodynamics of Linezolid in Adults and Children with Tuberculous Meningitis Litjens, Carlijn H. C. Verscheijden, Laurens F. M. Svensson, Elin M. van den Broek, Petra H. H. van Hove, Hedwig Koenderink, Jan B. Russel, Frans G. M. Aarnoutse, Rob E. te Brake, Lindsey H. M. Antibiotics (Basel) Article Linezolid is used off-label for treatment of central nervous system infections. However, its pharmacokinetics and target attainment in cranial cerebrospinal fluid (CSF) in tuberculous meningitis patients is unknown. This study aimed to predict linezolid cranial CSF concentrations and assess attainment of pharmacodynamic (PD) thresholds (AUC:MIC of >119) in plasma and cranial CSF of adults and children with tuberculous meningitis. A physiologically based pharmacokinetic (PBPK) model was developed to predict linezolid cranial CSF profiles based on reported plasma concentrations. Simulated steady-state PK curves in plasma and cranial CSF after linezolid doses of 300 mg BID, 600 mg BID, and 1200 mg QD in adults resulted in geometric mean AUC:MIC ratios in plasma of 118, 281, and 262 and mean cranial CSF AUC:MIC ratios of 74, 181, and 166, respectively. In children using ~10 mg/kg BID linezolid, AUC:MIC values at steady-state in plasma and cranial CSF were 202 and 135, respectively. Our model predicts that 1200 mg per day in adults, either 600 mg BID or 1200 mg QD, results in reasonable (87%) target attainment in cranial CSF. Target attainment in our simulated paediatric population was moderate (56% in cranial CSF). Our PBPK model can support linezolid dose optimization efforts by simulating target attainment close to the site of TBM disease. MDPI 2023-04-03 /pmc/articles/PMC10135070/ /pubmed/37107064 http://dx.doi.org/10.3390/antibiotics12040702 Text en © 2023 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 Litjens, Carlijn H. C. Verscheijden, Laurens F. M. Svensson, Elin M. van den Broek, Petra H. H. van Hove, Hedwig Koenderink, Jan B. Russel, Frans G. M. Aarnoutse, Rob E. te Brake, Lindsey H. M. Physiologically-Based Pharmacokinetic Modelling to Predict the Pharmacokinetics and Pharmacodynamics of Linezolid in Adults and Children with Tuberculous Meningitis |
title | Physiologically-Based Pharmacokinetic Modelling to Predict the Pharmacokinetics and Pharmacodynamics of Linezolid in Adults and Children with Tuberculous Meningitis |
title_full | Physiologically-Based Pharmacokinetic Modelling to Predict the Pharmacokinetics and Pharmacodynamics of Linezolid in Adults and Children with Tuberculous Meningitis |
title_fullStr | Physiologically-Based Pharmacokinetic Modelling to Predict the Pharmacokinetics and Pharmacodynamics of Linezolid in Adults and Children with Tuberculous Meningitis |
title_full_unstemmed | Physiologically-Based Pharmacokinetic Modelling to Predict the Pharmacokinetics and Pharmacodynamics of Linezolid in Adults and Children with Tuberculous Meningitis |
title_short | Physiologically-Based Pharmacokinetic Modelling to Predict the Pharmacokinetics and Pharmacodynamics of Linezolid in Adults and Children with Tuberculous Meningitis |
title_sort | physiologically-based pharmacokinetic modelling to predict the pharmacokinetics and pharmacodynamics of linezolid in adults and children with tuberculous meningitis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10135070/ https://www.ncbi.nlm.nih.gov/pubmed/37107064 http://dx.doi.org/10.3390/antibiotics12040702 |
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