PI-015 - IMPACT OF RIFAMPICIN DOSE ON LINEZOLID PHARMACOKINETICS IN TUBERCULOUS MENINGITIS: INSIGHTS FROM THE ALTER TRIAL

D. Purohit¹, F. Chow², R. Savic^3,4, R. Van Wijk⁵, P. Nahid³, F. Kibengo⁶, P. Kafeero⁶, P. Muhumuza⁶, M. Nakimbugwe⁶, A. Ssemaganda⁶, C. Tayebwa⁶, M. Zimmerman⁷, F. Cresswell⁸, V. Dartois⁹; ¹University of California, San Francsico, San Francisco, CA, United States, ²University of California, San Francsico, San Francisco, California, United States, ³University of California, San Francisco, San Francisco, CA, United States, ⁴UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, CA, United States, ⁵Leiden University, Leiden, Zuid-Holland, Netherlands, ⁶MRC/UVRI & LSHTM Uganda Research Unit, Masaka, Uganda, Uganda, ⁷The Hackensack Meridian Health Center for Discovery and Innovation (CDI), Nutley, New Jersey, United States, ⁸London School of Hygiene & Tropical Medicine, London, England, United Kingdom, ⁹The Hackensack Meridian Health Center for Discovery and Innovation (CDI), Nutley, New Jerset, United States.

Background: Tuberculous meningitis (TBM) is the most severe form of extrapulmonary tuberculosis, characterized by infection of the meninges surrounding the central nervous system. Despite current standard-of-care therapy, TBM is associated with high rates of morbidity and mortality. There remains uncertainty regarding whether adjunctive linezolid or higher doses of rifampicin could improve treatment outcomes. However, co-administration of these drugs raises concerns about drug-drug interactions, particularly through the induction of hepatic CYP3A4 enzymes, which may reduce drug exposure. This study aimed to evaluate the pharmacokinetics (PK) of linezolid in cerebrospinal fluid (CSF) and plasma in participants from the ALTER trial (NCT04021121).

Methods: The ALTER trial was a phase II, randomized, open-label study conducted at Masaka Regional Referral Hospital, Uganda. Participants received either high-dose (35 mg/kg) or standard-dose (10 mg/kg) rifampicin for 4 weeks, with a second randomization to receive either linezolid (1200 mg daily) or no linezolid. Standard TBM treatment included isoniazid, pyrazinamide, ethambutol, corticosteroids, and vitamin B6.

PK sampling involved CSF collection on Days 2, 14, and optionally on Day 28, along with plasma sampling. Nonlinear mixed-effects models described linezolid pharmacokinetics and estimated secondary parameters in plasma and CSF.

Results: Eighteen participants (median age: 38.5 years, range: 26–72) were included; all were living with HIV, with six on ART. The median weight at pharmacokinetic sampling was 50 kg (range: 34–69 kg). Linezolid clearance was 6.24 L/hr, the volume of distribution was 24.97 L, and the absorption rate constant was 0.35 hr-1. The equilibration rate constant to CSF was 0.382 hr-1, and the CSF partition coefficient was 53.81%. Covariate analysis showed that 300 mg of rifampicin reduced linezolid clearance by 30.75%, while doses of 1650–2100 mg increased clearance by 29.61%.

Conclusion: Increasing rifampicin doses may reduce plasma linezolid concentrations while maintaining CSF partitioning and entry rates. Model-based simulations suggest that higher rifampicin doses could still achieve adequate linezolid brain concentrations by adopting twice-daily dosing instead of once-daily administration.