Linezolid Population Pharmacokinetic Model in Plasma and Cerebrospinal Fluid Among Patients With Tuberculosis Meningitis.
J Infect Dis
; 229(4): 1200-1208, 2024 Apr 12.
Article
em En
| MEDLINE
| ID: mdl-37740554
ABSTRACT
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 (35â mg/kg) plus 1200â mg/day of linezolid for 28 days, which was then reduced to 600â 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 27.2â mg/L. Rifampicin cotreatment duration did not affect linezolid pharmacokinetics. CSF-plasma partitioning correlated with CSF total protein up to 1.2â g/L, where the partition coefficient reached a maximal value of 37%. The plasma-CSF equilibration half-life was â¼3.5 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).Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Rifampina
/
Tuberculose Meníngea
Tipo de estudo:
Prognostic_studies
Limite:
Adult
/
Humans
Idioma:
En
Revista:
J Infect Dis
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
África do Sul