{"doi":"10.1093/infdis/jiaf178","title":"Population Pharmacokinetics of Rifampicin in Plasma and Cerebrospinal Fluid in Adults With Tuberculosis Meningitis","abstract":"BACKGROUND: Several ongoing clinical trials are evaluating high-dose rifampicin (up to 35 mg/kg) for tuberculous meningitis (TBM). However, rifampicin pharmacokinetics at higher doses is not fully characterized, particularly in cerebrospinal fluid (CSF), the site of TBM disease. METHODS: In a randomized controlled trial, adults with HIV-associated TBM were assigned to experimental arms of high-dose rifampicin (oral, 35 mg/kg; intravenous, 20 mg/kg) plus linezolid, with or without aspirin, or a control arm that received the standard of care with 10 mg/kg of oral rifampicin. Rifampicin concentrations, including the unbound fraction, were measured on plasma samples, and CSF was collected on days 3 and 28 of study enrollment. Data were analyzed by nonlinear mixed effects modeling. RESULTS: In total, 400 plasma and 44 CSF rifampicin concentrations from 48 participants were used for model development. The median (range) age and weight were 39 years (25-78) and 60 kg (30-107). Rifampicin pharmacokinetics was best described by a 2-compartment disposition model with first-order transit oral absorption and elimination via saturable hepatic extraction. Typical clearance values for the standard dose for days 3 and 28 were 33.1 and 41.4 L/h, respectively; high-dose values were 46.1 and 70.2 L/h. The CSF-plasma ratio was approximately 6% and the equilibration half-life was 3.2 hours. Simulated standard-dose rifampicin did not reach CSF concentrations above the critical concentration for Mycobacterium tuberculosis. CONCLUSIONS: CSF penetration with standard-dose rifampicin is low. Our findings support continued evaluation of high-dose rifampicin for TBM treatment.","journal":"The Journal of Infectious Diseases","year":2025,"id":513788,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9581,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":308893,"name":"Sean Wasserman","orcid":"0000-0002-3508-6719","position":1,"is_corresponding":false},{"id":376088,"name":"Kamunkhwala Gausi","orcid":"0000-0002-9002-8087","position":2,"is_corresponding":false},{"id":418470,"name":"Angharad Davis","orcid":"0000-0001-8914-5094","position":3,"is_corresponding":false},{"id":560703,"name":"Cari Stek","orcid":"0000-0001-8813-0819","position":4,"is_corresponding":false},{"id":308898,"name":"Lubbe Wiesner","orcid":"0000-0002-9070-8699","position":5,"is_corresponding":false},{"id":292884,"name":"Graeme Meintjes","orcid":"0000-0003-1196-4414","position":6,"is_corresponding":false},{"id":266683,"name":"Robert J. Wilkinson","orcid":"0000-0002-2753-1800","position":7,"is_corresponding":false},{"id":308900,"name":"Paolo Denti","orcid":"0000-0001-7494-079X","position":8,"is_corresponding":false},{"id":969202,"name":"Noha Abdelgawad","orcid":"0000-0002-4907-345X","position":0,"is_corresponding":true}],"reference_count":28,"raw_metadata":null,"created_at":"2026-07-19T02:48:23.284782Z","pmid":"40295169","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}