{"doi":"10.1101/2025.07.14.25331510","title":"Pharmacokinetics of dexamethasone in tuberculosis meningitis","abstract":"Introduction: Dexamethasone is recommended as adjunctive therapy for tuberculosis meningitis (TBM). Co-administration with rifampicin is expected to reduce dexamethasone exposure in TBM, an effect that may be more pronounced with the higher rifampicin doses currently being evaluated in clinical trials. Methods: This pharmacokinetic study was nested in a randomised controlled trial comparing the safety of high-dose rifampicin (oral, 35 mg/kg; intravenous, 20 mg/kg) plus linezolid, with or without aspirin, vs standard-dose rifampicin (10 mg/kg) for adults with HIV-associated TBM. All participants received adjunctive oral dexamethasone every 12 hours starting at a dose of 0.4 mg/kg/day. Dexamethasone concentrations were measured on intensively sampled plasma on day 3 after study enrolment and analysed using nonlinear mixed-effects modelling. Results: In total, 261 dexamethasone concentrations from 43 participants were available for model development. Eight (18%) participants were on efavirenz-based ART and five (11%) were on a lopinavir/ritonavir-based regimen. The median duration of rifampicin therapy at the time of pharmacokinetic sampling was 4 days (range: 0-7). Dexamethasone pharmacokinetics was best described by a one-compartment disposition model with first-order absorption and elimination. Typical oral clearance (CL/F) was 131 L/h, reduced to 11.5 L/h with concomitant lopinavir/ritonavir. High-dose rifampicin had no significant additional effect on dexamethasone pharmacokinetic parameters compared with the standard-dose. Conclusions: In adults with HIV-associated TBM, there was high dexamethasone clearance, likely related to a drug-drug interaction with rifampicin. High-dose rifampicin had no additional effect on dexamethasone exposure.","journal":"medRxiv","year":2025,"id":570336,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9591,"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":1128019,"name":"Juan Eduardo Reséndiz‐Galván","orcid":"0000-0001-9111-8052","position":1,"is_corresponding":false},{"id":969202,"name":"Noha Abdelgawad","orcid":"0000-0002-4907-345X","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":308893,"name":"Sean Wasserman","orcid":"0000-0002-3508-6719","position":9,"is_corresponding":false},{"id":1427227,"name":"José Miguel Calderín Miranda","orcid":"0000-0002-0310-6949","position":0,"is_corresponding":true}],"reference_count":25,"raw_metadata":null,"created_at":"2026-07-19T02:57:07.857542Z","pmid":"40791718","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":[]}