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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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.
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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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