{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:20:20Z","timestamp":1768569620558,"version":"3.49.0"},"posted":{"date-parts":[[2025,7,15]]},"group-title":"Infectious Diseases (except HIV\/AIDS)","reference-count":25,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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\u20137). 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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>40-word summary of the article\u2019s main point<\/jats:title>\n                  <jats:p>This pharmacokinetic analysis of dexamethasone in adults with HIV-associated tuberculosis meningitis found high oral clearance (131 L\/h), likely due to a drug-drug interaction with rifampicin. High-dose rifampicin had no additional effect on dexamethasone exposure compared with standard dose.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.14.25331510","type":"posted-content","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T20:35:48Z","timestamp":1752611748000},"source":"Crossref","is-referenced-by-count":0,"title":["Pharmacokinetics of dexamethasone in tuberculosis meningitis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0310-6949","authenticated-orcid":false,"given":"Jose M","family":"Calderin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9111-8052","authenticated-orcid":false,"given":"Juan Eduardo","family":"Resendiz-Galvan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4907-345X","authenticated-orcid":false,"given":"Noha","family":"Abdelgawad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8914-5094","authenticated-orcid":false,"given":"Angharad","family":"Davis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8813-0819","authenticated-orcid":false,"given":"Cari","family":"Stek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9070-8699","authenticated-orcid":false,"given":"Lubbe","family":"Wiesner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1196-4414","authenticated-orcid":false,"given":"Graeme","family":"Meintjes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2753-1800","authenticated-orcid":false,"given":"Robert J.","family":"Wilkinson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7494-079X","authenticated-orcid":false,"given":"Paolo","family":"Denti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3508-6719","authenticated-orcid":false,"given":"Sean","family":"Wasserman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025071706400551000_2025.07.14.25331510v1.1","doi-asserted-by":"crossref","first-page":"e0000069","DOI":"10.1371\/journal.pgph.0000069","article-title":"The global burden of tuberculous meningitis in adults: A modelling study","volume":"1","year":"2021","journal-title":"PLOS Global Public Health"},{"key":"2025071706400551000_2025.07.14.25331510v1.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa040573"},{"key":"2025071706400551000_2025.07.14.25331510v1.3","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1056\/NEJMoa2216218","article-title":"Adjunctive Dexamethasone for Tuberculous Meningitis in HIV-Positive Adults","volume":"389","year":"2023","journal-title":"New England Journal of Medicine"},{"key":"2025071706400551000_2025.07.14.25331510v1.4","doi-asserted-by":"crossref","unstructured":"Prasad K , Singh MB , Ryan H . 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