{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T20:49:33Z","timestamp":1790887773016,"version":"4.1.0"},"reference-count":36,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["098316 and 203135\/Z\/16\/Z"],"award-info":[{"award-number":["098316 and 203135\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001728","name":"Swedish Foundation for International Cooperation in Research and Higher Education","doi-asserted-by":"publisher","award":["101575"],"award-info":[{"award-number":["101575"]}],"id":[{"id":"10.13039\/501100001728","id-type":"DOI","asserted-by":"publisher"}]},{"name":"South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation","award":["64787"],"award-info":[{"award-number":["64787"]}]},{"name":"NRF incentive funding","award":["85858"],"award-info":[{"award-number":["85858"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2026,4,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>Drug resistance (DR) poses a critical challenge to global efforts to manage tuberculosis (TB). Limited information is available on the combined cardiotoxicity of bedaquiline (BDQ), pretomanid (Pa), and clofazimine (CFZ), key drugs in current DR-TB treatment regimens. All of those prolong the QT interval. We aimed to describe this interaction to predict possible toxicities with established and novel dosing regimens to identify patients at higher risk of QT prolongation. The data for this analysis were obtained from an early-bactericidal activity study in drug-susceptible-TB of several TB drugs. We developed a competitive interaction model to evaluate combined concentration-QTc effect of all three drugs. The model was developed using ECG-matched PK measurements (105 patients, 2,062 observations). The model identified a maximum QT increase by all three drugs of 44.5 ms with respective EC50 values for BDQ, Pa, and CFZ of 0.57, 0.903, and 26.9 mg\/L. For patients aged 70 years with non-black ancestry, at risk of increased BDQ exposure, simulations showed that 39.1% had a drug-induced QT change &gt;30 ms after the loading period; this was 29.4% for following BDQ 400 mg daily regimen (part of UNITE4TB program). Reassuringly, no simulations resulted in a QTcF &gt;500 ms, and less than 1% exceeded 480 ms or a change from baseline of &gt;60 ms. We present a joint concentration-QT model of BDQ, Pa, and CFZ. The competitive interaction model serves as a tool to predict possible combined exposure-induced QT prolongation of these drugs in different dosing regimen and identify patients at high risk of significant QT-prolongation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.01399-25","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T14:00:21Z","timestamp":1773064821000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Exposure-QTc modeling of bedaquiline, pretomanid, and clofazimine in adults with tuberculosis"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2134-8749","authenticated-orcid":true,"given":"Mahmoud Tareq","family":"Abdelwahab","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03p74gp79","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town","place":["Cape Town, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0093-6445","authenticated-orcid":true,"given":"Elin M.","family":"Svensson","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05wg1m734","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacy, Pharmacology and Toxicology, Radboud University Medical Center","place":["Nijmegen, the Netherlands"]},{"id":[{"id":"https:\/\/ror.org\/048a87296","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacy, Uppsala University","place":["Uppsala, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas H.","family":"Diacon","sequence":"additional","affiliation":[{"name":"Task","place":["Bellville, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Almarie","family":"Conradie","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03ms7cf36","id-type":"ROR","asserted-by":"publisher"}],"name":"Global Alliance for TB Drug Development","place":["New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morounfolu","family":"Olugbosi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03ms7cf36","id-type":"ROR","asserted-by":"publisher"}],"name":"Global Alliance for TB Drug Development","place":["New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodney","family":"Dawson","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/016978714","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Pulmonology and Department of Medicine, University of Cape Town Lung Institute","place":["Cape Town, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3080-6606","authenticated-orcid":true,"given":"Gary","family":"Maartens","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03p74gp79","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town","place":["Cape Town, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7494-079X","authenticated-orcid":true,"given":"Paolo","family":"Denti","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03p74gp79","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town","place":["Cape Town, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","unstructured":"World Health Organization (WHO). 2023. Global tuberculosis report 2023 January. Geneva"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-024-00504-2"},{"key":"e_1_3_3_4_2","series-title":"WHO Press 2022 Update","volume-title":"WHO consolidated guidelines on tuberculosis","author":"World Health Organization (WHO)","year":"2022","unstructured":"World Health Organization (WHO). 2022. WHO consolidated guidelines on tuberculosis. WHO Press 2022 Update. World Health Organization, Geneva PP - Geneva."},{"key":"e_1_3_3_5_2","unstructured":"World Health Organization (WHO). 2022. WHO consolidated guidelines on tuberculosis. WHO Press 98"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12147"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dku171"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01418-13"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12722"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofac372"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00907-19"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02359-17"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00445-19"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkaa310"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02687-20"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiaf057"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1100488"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1177\/2042098612454283"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01207-2016"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2019.06.005"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61080-0"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12640"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1023\/a:1022972420004"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3536"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1901814"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01196-20"},{"key":"e_1_3_3_27_2","unstructured":"ICH. 2005. The clinical evaluation of QT \/ QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. Available from: http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Scientific_guideline\/2009\/09\/WC500002879.pdf"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiac024"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1177\/2045125317721662"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40264-016-0477-y"},{"key":"e_1_3_3_31_2","volume-title":"Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts and Applications","author":"Gabrielsson J","year":"2016","unstructured":"Gabrielsson J, Weiner D. 2016. Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts and Applications. 5th ed. Swedish Pharmaceutical Society.","edition":"5"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2685"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.70047"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-008-9088-2"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacep.2016.12.005"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2025.107460"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jctube.2022.100320"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.01399-25","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.01399-25","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T13:01:54Z","timestamp":1775048514000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/aac.01399-25"}},"subtitle":[],"editor":[{"given":"Cesar A.","family":"Arias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,4,1]]},"references-count":36,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4,1]]}},"alternative-id":["10.1128\/aac.01399-25"],"URL":"https:\/\/doi.org\/10.1128\/aac.01399-25","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,1]]},"assertion":[{"value":"2025-09-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01399-25"}}