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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-04-01
|
| Series: | Antibiotics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2079-6382/12/4/702 |
| _version_ | 1827746160388866048 |
|---|---|
| author | Carlijn H. C. Litjens Laurens F. M. Verscheijden Elin M. Svensson Petra H. H. van den Broek Hedwig van Hove Jan B. Koenderink Frans G. M. Russel Rob E. Aarnoutse Lindsey H. M. te Brake |
| author_facet | Carlijn H. C. Litjens Laurens F. M. Verscheijden Elin M. Svensson Petra H. H. van den Broek Hedwig van Hove Jan B. Koenderink Frans G. M. Russel Rob E. Aarnoutse Lindsey H. M. te Brake |
| author_sort | Carlijn H. C. Litjens |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T05:18:35Z |
| format | Article |
| id | doaj.art-1cda5fe5ffa44c3da3aedc061453a16f |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-11T05:18:35Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-1cda5fe5ffa44c3da3aedc061453a16f2023-11-17T18:02:46ZengMDPI AGAntibiotics2079-63822023-04-0112470210.3390/antibiotics12040702Physiologically-Based Pharmacokinetic Modelling to Predict the Pharmacokinetics and Pharmacodynamics of Linezolid in Adults and Children with Tuberculous MeningitisCarlijn H. C. Litjens0Laurens F. M. Verscheijden1Elin M. Svensson2Petra H. H. van den Broek3Hedwig van Hove4Jan B. Koenderink5Frans G. M. Russel6Rob E. Aarnoutse7Lindsey H. M. te Brake8Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The NetherlandsDepartment of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The NetherlandsDepartment of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The NetherlandsDepartment of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The NetherlandsDepartment of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The NetherlandsDepartment of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The NetherlandsDepartment of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The NetherlandsDepartment of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The NetherlandsDepartment of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The NetherlandsLinezolid 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.https://www.mdpi.com/2079-6382/12/4/702PBPKlinezolidtuberculous meningitis |
| spellingShingle | Carlijn H. C. Litjens Laurens F. M. Verscheijden Elin M. Svensson Petra H. H. van den Broek Hedwig van Hove Jan B. Koenderink Frans G. M. Russel Rob E. Aarnoutse Lindsey H. M. te Brake Physiologically-Based Pharmacokinetic Modelling to Predict the Pharmacokinetics and Pharmacodynamics of Linezolid in Adults and Children with Tuberculous Meningitis Antibiotics PBPK linezolid 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 | PBPK linezolid tuberculous meningitis |
| url | https://www.mdpi.com/2079-6382/12/4/702 |
| work_keys_str_mv | AT carlijnhclitjens physiologicallybasedpharmacokineticmodellingtopredictthepharmacokineticsandpharmacodynamicsoflinezolidinadultsandchildrenwithtuberculousmeningitis AT laurensfmverscheijden physiologicallybasedpharmacokineticmodellingtopredictthepharmacokineticsandpharmacodynamicsoflinezolidinadultsandchildrenwithtuberculousmeningitis AT elinmsvensson physiologicallybasedpharmacokineticmodellingtopredictthepharmacokineticsandpharmacodynamicsoflinezolidinadultsandchildrenwithtuberculousmeningitis AT petrahhvandenbroek physiologicallybasedpharmacokineticmodellingtopredictthepharmacokineticsandpharmacodynamicsoflinezolidinadultsandchildrenwithtuberculousmeningitis AT hedwigvanhove physiologicallybasedpharmacokineticmodellingtopredictthepharmacokineticsandpharmacodynamicsoflinezolidinadultsandchildrenwithtuberculousmeningitis AT janbkoenderink physiologicallybasedpharmacokineticmodellingtopredictthepharmacokineticsandpharmacodynamicsoflinezolidinadultsandchildrenwithtuberculousmeningitis AT fransgmrussel physiologicallybasedpharmacokineticmodellingtopredictthepharmacokineticsandpharmacodynamicsoflinezolidinadultsandchildrenwithtuberculousmeningitis AT robeaarnoutse physiologicallybasedpharmacokineticmodellingtopredictthepharmacokineticsandpharmacodynamicsoflinezolidinadultsandchildrenwithtuberculousmeningitis AT lindseyhmtebrake physiologicallybasedpharmacokineticmodellingtopredictthepharmacokineticsandpharmacodynamicsoflinezolidinadultsandchildrenwithtuberculousmeningitis |