PII-019 - LINEZOLID REACHES TARGET SITE IN TUBERCULOUS MENINGITIS PATIENTS IRRESPECTIVE OF STANDARD OR HIGH RIFAMPIN DOSE.

R. van Wijk¹, F. Kibengo², P. Kafeero², A. Kabarambi², P. Muhumuza², M. Nakimbugwe², A. Ssemaganda², C. Tayebwa², M. Zimmerman³, F. Cresswell², V. Dartois⁴, P. Nahid¹, R. Savic¹, F. Chow¹; ¹University of California, San Francisco, San Francisco, CA, USA, ²Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine, Uganda Research Unit, Entebbe, Uganda, ³Hackensack Meridian Health, Hackensack, NJ, USA, ⁴Hackensack Meridian Health, Nutley, NJ, USA.

Background: Tuberculous meningitis (TBM) is a devastating form of tuberculosis. Several anti-TBM medications poorly penetrate the cerebrospinal fluid (CSF). Linezolid has good CSF penetration. We assessed the linezolid pharmacokinetics (PK) from the ALTER trial, an ongoing Phase II, open-label, randomized clinical trial (NCT04021121) of adjunctive linezolid with high (35 mg/kg) or standard (10 mg/kg) dose rifampin in TBM patients.

Methods: Participants (≥18 years) recruited from Masaka, Uganda were randomized 1:1 to high versus standard dose rifampin, and then 1:1 to linezolid 1200 mg versus no linezolid for the first 4 weeks of treatment, all with a background regimen of isoniazid, pyrazinamide, and ethambutol. CSF and plasma were sampled on days 2, 14 and/or 28. Population PK modelling was used to quantify linezolid plasma and CSF exposure, testing demographics and rifampin dose as covariates.

Results: Of the first 15 enrolled participants (53% women, median age 37, median weight 50 kg), median linezolid CSF and plasma peak concentrations were 3.20 and 11.0 ug/mL, respectively. The PK was best described by a one compartment (distribution volume 46.1 L) model with first-order absorption (6.86 h-1), and allometrically scaled clearance (7.95 L/h) with inter-individual variability. Women had 35.8% lower clearance than men. Plasma-to-CSF rate was fast, and the partition coefficient was 54.6%. High dose rifampin did not significantly impact linezolid disposition parameters.

Conclusion: Linezolid reaches the target site (brain) in TBM patients irrespective of rifampin dose as shown by our model-based analysis of preliminary trial data. Upon trial completion, our workflow will be used to confirm these results and to determine efficacy target exposure achievement through clinical trial simulations.