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

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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) where exposures may be affected by changes in protein concentration. Linezolid co-administration with high-dose rifampicin, has also not been studied. We aimed to characterize linezolid plasma and CSF pharmacokinetics in adults with TBM. METHODS: In LASER-TBM pharmacokinetic-substudy, the intervention groups received high-dose rifampicin (35mg/kg) plus linezolid 1200mg/day for 28days, then reduced to 600mg/day. Plasma sampling was done on day 3 (intensive) and on day 28 (sparse). A lumbar CSF sample was obtained on both visits. RESULTS: 30-participants, median(min-max) age and weight of 40(27-56)years and 58(30-96)kg, contributed 247 plasma and 28 CSF observations. Plasma pharmacokinetics was described by one-compartment model with first-order absorption and saturable elimination. Maximal clearance was 7.25L/h, and Km was 27.2mg/L. Rifampicin co-treatment duration did not affect linezolid pharmacokinetics. CSF-Plasma partitioning correlated with CSF total-protein upto 1.2g/L where the partition-coefficient reached maximal value of 37%. Plasma-CSF equilibration half-life was ∼3.5hours. CONCLUSION: Linezolid was readily detected in CSF despite high-dose rifampicin co-administration. These findings support continued clinical evaluation of linezolid plus high-dose rifampicin for the treatment of TBM in adults.

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