Pharmacokinetic Study of Linezolid for TB Meningitis
Status:
Recruiting
Trial end date:
2023-07-01
Target enrollment:
Participant gender:
Summary
Tuberculosis meningitis (TBM) is the most severe manifestation of TB, resulting in death or
neurological disability in up to 50% of affected patients, despite antibacterial treatment.
This TBM treatment follows the model for pulmonary TB by using the same first-line TB drugs
(a combination of rifampicin, isoniazid, pyrazinamide and ethambutol) and the same dosing
guidelines, although it is known that penetration of two of these drugs (rifampicin and
ethambutol) into cerebrospinal fluid (CSF) is limited. Improvement of treatment of TBM is
urgently needed.
To do so, a combination of two interventions will be investigated in this study. A series of
phase II clinical trials on higher doses of the pivotal TB drug rifampicin in Indonesian
patients with TBM have shown that the dose of rifampicin can be increased from 10 mg/kg
orally (standard dose) up to 30 mg/kg orally, resulting in a strong increase in exposure to
this drug in plasma and CSF, no increase in grade III or IV adverse effects, and a reduction
in mortality. Similarly, higher doses of rifampicin up to 35 mg/kg resulted in strong
increases in plasma concentrations; the doses were well tolerated and reduced time to sputum
conversion in African pulmonary TB patients.
Next to a higher dose of rifampicin, the approved antibacterial drug linezolid seems a good
candidate for a new TBM regimen. The drug penetrates well into the CSF and is applied
successfully against other central nervous system (CNS) infections (e.g. caused by
penicillin-nonsusceptible Streptococcus pneumoniae, vancomycin-resistant enterococci and
methicillin-resistant Staphylococcus aureus). In a study in China, linezolid in a dose of 600
mg BID orally strongly increased recovery of patients with TBM response. Linezolid is also
being investigated as a new drug for (drug-resistant) pulmonary TB in numerous studies, in a
dose of 1200 mg once daily. More severe adverse effects to this drug typically occur only
after prolonged treatment during several months, not during short-term treatment.
Overall, linezolid is expected to be a promising and tolerable candidate for a new
intensified TBM treatment regimen consisting of a backbone of high dose rifampicin plus
linezolid.
Phase:
Phase 2
Details
Lead Sponsor:
Universitas Padjadjaran
Collaborators:
Global Alliance for TB Drug Development Radboud University