Population pharmacokinetics of pyrazinamide and isoniazid in plasma and cerebrospinal fluid from South African adults with tuberculous meningitis
Author(s)
Type
Journal Article
Abstract
Pyrazinamide and isoniazid are first-line drugs for tuberculous meningitis (TBM), but limited information is available on their plasma pharmacokinetics, and particularly cerebrospinal fluid (CSF) penetration, in patients with TBM. Any potential effect of co-administration with high-dose rifampicin, also being evaluated in trials for TBM, is unknown. Understanding this is important for dose optimisation. We characterized pyrazinamide and isoniazid plasma and CSF pharmacokinetics among adults enrolled in a phase 2 clinical trial of intensified antibiotic therapy for HIV-associated TBM. Participants were randomized to receive either standard TBM treatment (including rifampicin 10 mg/kg) or high-dose rifampicin (35 mg/kg) plus linezolid, with or without aspirin. Plasma and lumbar CSF samples were collected on days 3 and 28 after study enrollment, and drug concentrations were measured using liquid chromatography-tandem mass spectrometry. Data were analysed using nonlinear mixed-effects modeling. Forty-nine participants provided 414 plasma and 44 CSF concentrations. Pyrazinamide CSF concentrations equilibrated with plasma with a half-life of 0.66 h and a pseudo-partition coefficient of 1.05. Isoniazid concentrations equilibrated with a half-life of 3.87 h and a pseudo-partition coefficient of 1.04. Pyrazinamide clearance increased by 30% from day 3 to day 28. NAT2 phenotype determined multi-modal isoniazid clearance. High-dose rifampicin did not affect pyrazinamide or isoniazid plasma pharmacokinetics or CSF penetration. Both drugs achieved exposure in CSF similar to plasma, supporting their crucial role in TBM treatment. Plasma pharmacokinetics of pyrazinamide and isoniazid in TBM were consistent with previously reported values in pulmonary tuberculosis, even when co-administered with high-dose rifampicin.
Editor(s)
Doernberg, Sarah
Date Issued
2025-08-06
Date Acceptance
2025-05-19
Citation
Antimicrobial Agents and Chemotherapy, 2025, 69 (8)
ISSN
0066-4804
Publisher
American Society for Microbiology
Journal / Book Title
Antimicrobial Agents and Chemotherapy
Volume
69
Issue
8
Copyright Statement
© 2025 Calderin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40590723
Subjects
BLOOD-BRAIN-BARRIER
cerebrospinal fluid penetration
DRUGS
high-dose rifampicin
isoniazid
Life Sciences & Biomedicine
Microbiology
NAT2 phenotype
nonlinear mixed-effects modeling
NONMEM
Pharmacology & Pharmacy
population pharmacokinetics
pyrazinamide
QUANTIFICATION
RIFAMPICIN
Science & Technology
tuberculous meningitis
Publication Status
Published
Coverage Spatial
United States
Article Number
e00099-25
Date Publish Online
2025-07-01