Linezolid Population Pharmacokinetic Model in Plasma and Cerebrospinal Fluid Among Patients With Tuberculosis Meningitis.
| Autor: | Abdelgawad N; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa., Wasserman S; Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.; Institute for Infection and Immunity, St George's University of London, United Kingdom., Abdelwahab MT; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa., Davis A; Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.; The Francis Crick Institute, London, United Kingdom.; Faculty of Life Sciences, University College London, United Kingdom., Stek C; Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa., Wiesner L; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa., Black J; Department of Medicine, Walter Sisulu University, Mthatha, South Africa., Meintjes G; Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.; Department of Medicine, University of Cape Town, South Africa., Wilkinson RJ; Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.; Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, South Africa.; The Francis Crick Institute, London, United Kingdom.; Department of Infectious Diseases, Imperial College London, United Kingdom., Denti P; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa. |
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| Jazyk: | angličtina |
| Zdroj: | The Journal of infectious diseases [J Infect Dis] 2024 Apr 12; Vol. 229 (4), pp. 1200-1208. |
| DOI: | 10.1093/infdis/jiad413 |
| Abstrakt: | Background: Linezolid is evaluated in novel treatment regimens for tuberculous meningitis (TBM). Linezolid pharmacokinetics have not been characterized in this population, particularly in cerebrospinal fluid (CSF), as well as, following its co-administration with high-dose rifampicin. We aimed to characterize linezolid plasma and CSF pharmacokinetics in adults with TBM. Methods: In the LASER-TBM pharmacokinetic substudy, the intervention groups received high-dose rifampicin (35 mg/kg) plus 1200 mg/day of linezolid for 28 days, which was then reduced to 600 mg/day. Plasma sampling was done on day 3 (intensive) and day 28 (sparse). A lumbar CSF sample was obtained on both visits. Results: Thirty participants contributed 247 plasma and 28 CSF observations. Their median age and weight were 40 years (range, 27-56) and 58 kg (range, 30-96). Plasma pharmacokinetics was described by a 1-compartment model with first-order absorption and saturable elimination. Maximal clearance was 7.25 L/h, and the Michaelis-Menten constant was 27.2 mg/L. Rifampicin cotreatment duration did not affect linezolid pharmacokinetics. CSF-plasma partitioning correlated with CSF total protein up to 1.2 g/L, where the partition coefficient reached a maximal value of 37%. The plasma-CSF equilibration half-life was ∼3.5 hours. Conclusions: Linezolid was readily detected in CSF despite high-dose rifampicin coadministration. These findings support continued clinical evaluation of linezolid plus high-dose rifampicin for the treatment of TBM in adults. Clinical Trials Registration. ClinicalTrials.gov (NCT03927313). Competing Interests: Potential conflicts of interest . All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.) |
| Databáze: | MEDLINE |
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