{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:23:53Z","timestamp":1787009033389,"version":"build-2736575974"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T00:00:00Z","timestamp":1743120000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PanACEA-TB consortium","award":["TRIA2015-1102"],"award-info":[{"award-number":["TRIA2015-1102"]}]},{"name":"Veni project","award":["09150161910052"],"award-info":[{"award-number":["09150161910052"]}]},{"DOI":"10.13039\/501100003246","name":"Dutch Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"name":"German Ministry for Education and Research","award":["01KA1701"],"award-info":[{"award-number":["01KA1701"]}]},{"DOI":"10.13039\/100009139","name":"German Center for Infection Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009139","id-type":"DOI","asserted-by":"publisher"}]},{"name":"InfectControl","award":["03ZZ0803A"],"award-info":[{"award-number":["03ZZ0803A"]}]},{"name":"InfectControl","award":["03ZZ0835A"],"award-info":[{"award-number":["03ZZ0835A"]}]},{"name":"InfectControl","award":["03ZZ0826A"],"award-info":[{"award-number":["03ZZ0826A"]}]},{"name":"Bavarian Ministry for Science and the Arts"},{"name":"Swiss State Secretariat for Education, Research, and Innovation"},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,5,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>BTZ-043 is a first-in-class benzothiazinone for the treatment of TB with demonstrated early bactericidal activity. BTZ-043 is metabolized into two major metabolites: M1 and M2. The aim of this study was to characterize the pharmacokinetics (PK) and early exposure\u2013response (pharmacokinetic\/pharmacodynamic, PK\/PD) relationship for BTZ-043.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A population PK\/PD model for BTZ-043 and its metabolites was developed using data from a sequential Phase 1b\/2a, randomized, controlled clinical trial in participants with pulmonary TB. BTZ-043 was administered in daily doses ranging from 250 to 1750\u2005mg over 14\u2005days. The decrease in bacterial load was determined by culture of sputum samples to quantify cfu on solid medium, and time to positivity in liquid medium.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In total, 77 participants received the experimental treatment. PK were best described by two-compartment disposition models for BTZ-043 and M2, and a one-compartment disposition model for M1. When given without food, the bioavailability was 54% (95% CI: 43%\u201365%) lower than with food. The decrease in bacterial load was described by a bilinear model with estimated node at 48\u2005h. Participants in the highest dose group in Stage 2 (1000\u2005mg) had a 2-fold faster decrease in mycobacterial load during the initial 2\u2005days compared with participants in the lowest dose group (250\u2005mg), driven by an Emax relationship to the BTZ-043total exposure (BTZ-043\u200a+\u200aM2).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We characterized the population PK\/PD of BTZ-043 in trial participants with pulmonary TB. An exposure\u2013response relationship was only apparent for the first 2\u2005days on treatment, indicating the need for further dose-finding studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jac\/dkaf076","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T07:38:44Z","timestamp":1740728324000},"page":"1315-1323","source":"Crossref","is-referenced-by-count":4,"title":["Population pharmacokinetics and exposure\u2013response relationship of the antituberculosis drug BTZ-043"],"prefix":"10.1093","volume":"80","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7011-667X","authenticated-orcid":false,"given":"Simon E","family":"Koele","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Radboud Institute for Medical Innovation, Radboud University Medical Center , Nijmegen ,","place":["The 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LMU University Hospital, LMU , Munich ,","place":["Germany"]},{"name":"German Center for Infection Research (DZIF), Munich Partner Site , Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick P J","family":"Phillips","sequence":"additional","affiliation":[{"name":"UCSF Center for Tuberculosis, University of California San Francisco , San Francisco ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Gross-Demel","sequence":"additional","affiliation":[{"name":"Institute of Infectious Diseases and Tropical Medicine, LMU University Hospital, LMU , Munich ,","place":["Germany"]},{"name":"German Center for Infection Research (DZIF), Munich Partner Site , Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodney","family":"Dawson","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cape Town Lung Institute , Cape Town ,","place":["South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Narunsky","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cape Town Lung Institute , Cape Town ,","place":["South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia M","family":"Wildner","sequence":"additional","affiliation":[{"name":"UCL Centre for Clinical Microbiology, University College London , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy D","family":"Mchugh","sequence":"additional","affiliation":[{"name":"UCL Centre for Clinical Microbiology, University College London , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey H M","family":"Te Brake","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Radboud Institute for Medical Innovation, Radboud University Medical Center , Nijmegen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas H","family":"Diacon","sequence":"additional","affiliation":[{"name":"TASK , Cape Town ,","place":["South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob E","family":"Aarnoutse","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Radboud Institute for Medical Innovation, Radboud University Medical Center , Nijmegen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7642-1835","authenticated-orcid":false,"given":"Michael","family":"Hoelscher","sequence":"additional","affiliation":[{"name":"Institute of Infectious Diseases and Tropical Medicine, LMU University Hospital, LMU , Munich ,","place":["Germany"]},{"name":"German Center for Infection Research (DZIF), Munich Partner Site , Munich ,","place":["Germany"]},{"name":"Fraunhofer Institute for Translational 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