{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T03:02:08Z","timestamp":1783738928431,"version":"3.55.0"},"reference-count":33,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,2,29]],"date-time":"2020-02-29T00:00:00Z","timestamp":1582934400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:p>The most effective antituberculosis drug treatment regimen for tuberculous meningitis is uncertain. We conducted a randomized controlled trial comparing standard treatment with a regimen intensified by rifampin 15\u00a0mg\/kg and levofloxacin for the first 60\u00a0days. The intensified regimen did not improve survival or any other outcome. We therefore conducted a nested pharmacokinetic\/pharmacodynamic study in 237 trial participants to define exposure\u2013response relationships that might explain the trial results and improve future therapy. Rifampin 15\u00a0mg\/kg increased plasma and cerebrospinal fluid (CSF) exposures compared with 10\u00a0mg\/kg: day 14 exposure\u00a0increased from 48.2\u00a0hour\u00b7mg\/L (range 18.2\u201393.8) to 82.5\u00a0hour\u00b7mg\/L (range 8.7\u2013161.0) in plasma\u00a0and from 3.5\u00a0hour\u00b7mg\/L (range 1.2\u20139.6) to 6.0\u00a0hour\u00b7mg\/L (range 0.7\u201315.1)\u00a0in CSF. However, there was no relationship between rifampin exposure and survival. In contrast, we found that isoniazid exposure was associated with survival, with low exposure predictive of death, and was linked to a fast metabolizer phenotype. Higher doses of isoniazid should be investigated, especially in fast metabolizers.<\/jats:p>","DOI":"10.1002\/cpt.1783","type":"journal-article","created":{"date-parts":[[2020,1,20]],"date-time":"2020-01-20T03:55:06Z","timestamp":1579492506000},"page":"1023-1033","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Pharmacokinetics and Pharmacodynamics of Intensive Antituberculosis Treatment of Tuberculous Meningitis"],"prefix":"10.1111","volume":"107","author":[{"given":"Junjie","family":"Ding","sequence":"first","affiliation":[{"name":"Nuffield Department of Clinical Medicine Centre for Tropical Medicine and Global Health University of Oxford Oxford UK"},{"name":"The WorldWide Antimalarial Resistance Network Oxford UK"},{"name":"Mahidol\u2010Oxford Tropical Medicine Research Unit Faculty of Tropical Medicine Mahidol University Bangkok 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