{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:06:52Z","timestamp":1790762812782,"version":"4.1.0"},"reference-count":23,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000030","name":"U.S. Centers for Disease Control and Prevention","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000030","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005258","name":"National Center for HIV\/AIDS, Viral Hepatitis, STD, and TB Prevention","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005258","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Division of Tuberculosis Elimination","award":["200-2009-32582"],"award-info":[{"award-number":["200-2009-32582"]}]},{"name":"Division of Tuberculosis Elimination","award":["200-2009-32593"],"award-info":[{"award-number":["200-2009-32593"]}]},{"name":"Division of Tuberculosis Elimination","award":["200-2009-32594"],"award-info":[{"award-number":["200-2009-32594"]}]},{"name":"Division of Tuberculosis Elimination","award":["200-2009-32589"],"award-info":[{"award-number":["200-2009-32589"]}]},{"name":"Division of Tuberculosis Elimination","award":["200-2009-32597"],"award-info":[{"award-number":["200-2009-32597"]}]},{"name":"Division of Tuberculosis Elimination","award":["200-2009-32598"],"award-info":[{"award-number":["200-2009-32598"]}]},{"name":"Division of Tuberculosis Elimination","award":["75D30119C06702"],"award-info":[{"award-number":["75D30119C06702"]}]},{"name":"Division of Tuberculosis Elimination","award":["75D30119C06701"],"award-info":[{"award-number":["75D30119C06701"]}]},{"name":"Division of Tuberculosis Elimination","award":["75D30119C06703"],"award-info":[{"award-number":["75D30119C06703"]}]},{"name":"Division of Tuberculosis Elimination","award":["75D30119C06222"],"award-info":[{"award-number":["75D30119C06222"]}]},{"name":"Division of Tuberculosis Elimination","award":["75D30119C06225"],"award-info":[{"award-number":["75D30119C06225"]}]},{"name":"Division of Tuberculosis Elimination","award":["75D30119C06010"],"award-info":[{"award-number":["75D30119C06010"]}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UM1 AI068634"],"award-info":[{"award-number":["UM1 AI068634"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UM1 AI068636"],"award-info":[{"award-number":["UM1 AI068636"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UM1 AI106701"],"award-info":[{"award-number":["UM1 AI106701"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Division of Tuberculosis Elimination"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Ethambutol, a longstanding treatment for tuberculosis (TB), lacks comprehensive pharmacokinetic (PK) data, particularly regarding covariates affecting exposure and their link to treatment outcomes. Using the largest data to date from Study 31\/AIDS Clinical Trials Group A5349, we aimed to characterize ethambutol PKs, identify risk factors for lower exposure, quantify relationships between exposure and efficacy and safety outcomes, and explore dosing considerations that optimize risks and benefits.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed ethambutol PK data using nonlinear mixed-effect modeling. We evaluated the contribution of ethambutol exposure to efficacy outcomes using parametric time-to-event modeling and safety outcomes using logistic regression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In 1493 participants with 3077 plasma samples, a one-compartment model with first-order elimination best described ethambutol PKs, with diabetes, higher creatinine clearance, and higher weight linked to increased clearance. Higher ethambutol exposure was modestly associated with grade 3 or higher adverse events and a reduced risk of TB-related unfavorable outcomes. Target exposures for 95% cure were 8.9\u2005\u00b5g\u00b7h\/mL in the 6-month control regimen and 25.6\u2005\u00b5g\u00b7h\/mL in the 4-month rifapentine regimen. Simulations showed that reducing doses in middle (1200 to 1000\u2005mg) and highest (1600 to 1200\u2005mg) weight bands could equalize median exposures, lowering toxicity risk while maintaining efficacy in the control regimen, but might not achieve target exposure in the rifapentine regimen.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The contribution of ethambutol exposure is regimen-dependent, with a higher efficacy target required for the 4-month rifapentine regimen. Dose reductions for patients above 55\u2005kg may mitigate toxicity in standard therapy but risk compromising efficacy in the shorter regimen.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/infdis\/jiag431","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T11:58:52Z","timestamp":1789473532000},"source":"Crossref","is-referenced-by-count":0,"title":["Ethambutol Population Pharmacokinetics and Pharmacodynamics From a Phase 3 Confirmatory Trial for the Treatment of Tuberculosis"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2248-1381","authenticated-orcid":false,"given":"Silver","family":"Alkhafaji","sequence":"first","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco , San Francisco, California ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2581-349X","authenticated-orcid":false,"given":"Eunsol","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco , San Francisco, California ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3867-654X","authenticated-orcid":false,"given":"Kaylee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco , San Francisco, California ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent K","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco , San Francisco, California ,","place":["USA"]},{"name":"UCSF Center for Tuberculosis, University of California, San Francisco , San Francisco, California ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6336-7024","authenticated-orcid":false,"given":"Patrick P J","family":"Phillips","sequence":"additional","affiliation":[{"name":"UCSF Center for Tuberculosis, University of California, San Francisco , San Francisco, California ,","place":["USA"]},{"name":"Division of Pulmonary and Critical Care Medicine, University of California, San Francisco , San Francisco, California ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2811-1311","authenticated-orcid":false,"given":"Payam","family":"Nahid","sequence":"additional","affiliation":[{"name":"UCSF Center for Tuberculosis, University of California, San Francisco , San Francisco, California ,","place":["USA"]},{"name":"Division of Pulmonary and Critical Care Medicine, University of California, San Francisco , San Francisco, California ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6882-9470","authenticated-orcid":false,"given":"Susan E","family":"Dorman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Medical University of South Carolina , Charleston, South Carolina ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Weiner","sequence":"additional","affiliation":[{"name":"San Antonio and the South Texas Veterans Health Care System, University of Texas Health Science Center , San Antonio, Texas ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina V","family":"Kurbatova","sequence":"additional","affiliation":[{"name":"Division of Tuberculosis Elimination, Centers for Disease Control and Prevention , Atlanta , ,","place":["Georgia USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0785-7800","authenticated-orcid":false,"given":"Kia","family":"Bryant","sequence":"additional","affiliation":[{"name":"Division of Tuberculosis Elimination, Centers for Disease Control and Prevention , Atlanta , ,","place":["Georgia USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Carr","sequence":"additional","affiliation":[{"name":"Division of Tuberculosis Elimination, Centers for Disease Control and Prevention , Atlanta , ,","place":["Georgia USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7740-8192","authenticated-orcid":false,"given":"Melissa L","family":"Engle","sequence":"additional","affiliation":[{"name":"San Antonio and the South Texas Veterans Health Care System, University of Texas Health Science Center , San Antonio, Texas ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Viet","family":"Nhung","sequence":"additional","affiliation":[{"name":"San Francisco Research Collaboration Unit, Vietnam National Tuberculosis Program\u2013University of California , Hanoi ,","place":["Vietnam"]},{"name":"University of Medicine and Pharmacy, Vietnam National University , Hanoi ,","place":["Vietnam"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pheona","family":"Nsubuga","sequence":"additional","affiliation":[{"name":"Uganda\u2013Case Western Reserve University Research Collaboration , Kampala ,","place":["Uganda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8641-6792","authenticated-orcid":false,"given":"Andreas","family":"Diacon","sequence":"additional","affiliation":[{"name":"TASK , Cape Town, Western Cape ,","place":["South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9013-5256","authenticated-orcid":false,"given":"Kelly E","family":"Dooley","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Vanderbilt University Medical Center , Nashville, Tennessee ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4710-925X","authenticated-orcid":false,"given":"Richard E","family":"Chaisson","sequence":"additional","affiliation":[{"name":"School of Medicine, Johns Hopkins University School of Medicine , Baltimore, Maryland ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5826-6037","authenticated-orcid":false,"given":"Susan","family":"Swindells","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of Nebraska Medical Center , Omaha, Nebraska 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