Linezolid population pharmacokinetic model in plasma and cerebrospinal fluid among patients with tuberculosis meningitis

Abstract

Background: Linezolid is being evaluated in novel treatment regimens for tuberculous meningitis (TBM). The pharmacokinetics of linezolid have not been characterized in this population, particularly in cerebrospinal fluid (CSF) where exposures may be affected by changes in protein concentration and rifampicin co-administration.

Methods: This was a sub-study of a phase 2 clinical trial of intensified antibiotic therapy for adults with HIV-associated TBM. Participants in the intervention groups received high-dose rifampicin (35 mg/kg) plus linezolid 1200 mg daily for 28 days followed by 600 mg daily until day 56. Plasma was intensively sampled, and lumbar CSF was collected at a single timepoint in a randomly allocated sampling window, within 3 days after enrolment. Sparse plasma and CSF samples were also obtained on day 28. Linezolid concentrations were analyzed using non-linear mixed effects modelling.

Results: 30 participants contributed 247 plasma and 28 CSF linezolid observations. Plasma PK was best described by a one-compartment model with first-order absorption and saturable elimination. The typical value of maximal clearance was 7.25 L/h. Duration of rifampicin co-treatment (compared on day 3 versus day 28) did not affect linezolid pharmacokinetics. Partitioning between plasma and CSF correlated with CSF total protein concentration up to 1.2 g/L where the partition coefficient reached a maximal value of 37%. The equilibration half-life between plasma and CSF was estimated at ∼3.5 hours.

Conclusion: Linezolid was readily detected in CSF despite co-administration of the potent inducer rifampicin at high doses. These findings support continued clinical evaluation of linezolid plus high-dose rifampicin for the treatment of TBM in adults.