{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T17:01:26Z","timestamp":1772816486881,"version":"3.50.1"},"reference-count":17,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2018,11,30]],"date-time":"2018-11-30T00:00:00Z","timestamp":1543536000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HHSN272200800026C"],"award-info":[{"award-number":["HHSN272200800026C"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Pharm in Drug Dev"],"published-print":{"date-parts":[[2019,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>There is an urgent need to identify safe and effective combination treatments for multidrug\u2010resistant (MDR) <jats:italic>Mycobacterium tuberculosis<\/jats:italic> infection (TB). Bedaquiline, a new diarylquinoline, is approved for the treatment of MDR pulmonary TB in combination with other drugs, which could include rifabutin, which is also used to treat drug\u2010resistant TB. Both rifabutin and bedaquiline are metabolized via cytochrome P450 3A4, and rifabutin is an inducer of this enzyme. Bedaquiline is metabolized into its primary <jats:italic>N<\/jats:italic>\u2010monodesmethyl metabolite, M2, and further desmethylated into an <jats:italic>N\u2010<\/jats:italic>didesmethyl metabolite, M3. Both metabolites are cytotoxic and induce phospholipidosis. The effect of rifabutin on the generation and disposition of the 2 metabolites was investigated in healthy adult volunteers coadministered bedaquiline and either rifabutin or rifampin. Subjects received single oral doses (400\u00a0mg) of bedaquiline on days 1 and 29. Oral rifabutin (300\u00a0mg) or rifampin (600\u00a0mg) were given daily on days 20\u201341. In the rifabutin group maximum M2 concentrations (C<jats:sub>max<\/jats:sub>) increased significantly (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.001) from 47.59 to 79.53\u00a0ng\/mL, and clearance slowed slightly (<jats:italic>P\u00a0<\/jats:italic>=\u00a0.01). This resulted in significantly (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.001) increased overall exposure (area under the concentration\u2010time curve [AUC<jats:sub>0\u2010\u03c4<\/jats:sub>]). Peak concentrations of M3 increased approximately 3\u2010fold with little decline thereafter. In rifampin recipients M2 C<jats:sub>max<\/jats:sub> doubled (48.44 to 101.52\u00a0ng\/mL), but M2 clearance and time to C<jats:sub>max<\/jats:sub> significantly (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.001) increased, and AUC<jats:sub>0\u2010\u221e<\/jats:sub> and mean residence time significantly decreased (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.001). Peak M3 concentrations increased 4\u2010fold and rapidly declined. Although both rifamycins accelerate desmethylation of bedaquiline and M2, differences in clearance resulted in sustained elevations of both metabolites during rifabutin, but not rifampin, treatment.<\/jats:p>","DOI":"10.1002\/cpdd.639","type":"journal-article","created":{"date-parts":[[2018,11,30]],"date-time":"2018-11-30T14:24:11Z","timestamp":1543587851000},"page":"436-442","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Effects of Rifamycin Coadministration on Bedaquiline Desmethylation in Healthy Adult Volunteers"],"prefix":"10.1002","volume":"8","author":[{"given":"Amanda M.","family":"Healan","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases and HIV Medicine Case Western Reserve University  Cleveland OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A.","family":"Salata","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and HIV Medicine Case Western Reserve University  Cleveland OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. McLeod","family":"Griffiss","sequence":"additional","affiliation":[{"name":"ClinicalRM  Hinckley OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Howard M.","family":"Proskin","sequence":"additional","affiliation":[{"name":"Howard M. Proskin and Associates, Inc  Rochester NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary Ann","family":"O'Riordan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Case Western Reserve University  Cleveland OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wesley A.","family":"Gray","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Toledo College of Medicine  Toledo OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey L.","family":"Blumer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Toledo College of Medicine  Toledo OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,11,30]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1106753"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0196756"},{"key":"e_1_2_7_4_1","unstructured":"U.S. Food and Drug Administration. December 31 2012. FDA news release. FDA Washington DC.http:\/\/www.fda.gov\/NewsEvents\/Newsroom\/PressAnnouncments\/ucm333695.htm. Accessed November 19 2018."},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0808427"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.06126-11"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dku171"},{"key":"e_1_2_7_8_1","unstructured":"FDA Office of Antimicrobial Products. November 28 2012. Briefing package NDA 204\u2013384 Sirturo (bedaquiline 100\u2010mg tablets) for the treatment of adults (\u2265 18 years) as part of combination therapy of pulmonary multi\u2010drug\u2010resistant tuberculosis (MDRTB). FDA Anti\u2010infective Drugs Advisory Committee Meeting. FDA Office of Antimicrobial Products Silver Spring MD."},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00720-11"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2012.08.013"},{"key":"e_1_2_7_11_1","unstructured":"World Health Organization.2010.Treatment of tuberculosis: guidelines. Geneva: WHO."},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-2797(97)00071-9"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2010.02.001"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200140050-00002"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04171-14"},{"key":"e_1_2_7_16_1","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1093\/jac\/dku504","article-title":"Rifampicin and rifapentine significantly reduce concentrations of bedaquiline, a new anti\u2010TB drug","volume":"70","author":"Svensson EM","year":"2015","journal-title":"J Antimicrob Chemother"},{"issue":"1","key":"e_1_2_7_17_1","doi-asserted-by":"crossref","first-page":"e00855","DOI":"10.1128\/AAC.00855-17","article-title":"Impact of rifabutin or rifampin on bedaquiline safety, tolerability, and pharmacokinetics: a randomized clinical trial in healthy adult volunteers","volume":"62","author":"Healan AM","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2012.10.021"}],"container-title":["Clinical Pharmacology in Drug Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcpdd.639","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpdd.639","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpdd.639","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpdd.639","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,10]],"date-time":"2023-09-10T08:15:15Z","timestamp":1694333715000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/cpdd.639"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,30]]},"references-count":17,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2019,5]]}},"alternative-id":["10.1002\/cpdd.639"],"URL":"https:\/\/doi.org\/10.1002\/cpdd.639","archive":["Portico"],"relation":{},"ISSN":["2160-763X","2160-7648"],"issn-type":[{"value":"2160-763X","type":"print"},{"value":"2160-7648","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,30]]},"assertion":[{"value":"2018-02-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-11-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-11-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}