{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T12:33:20Z","timestamp":1792154000526,"version":"4.4.0"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Aim<\/jats:title>\n                    <jats:p>The rise of drug\u2010resistant tuberculosis (TB) poses a need for new drugs and combinations. TBAJ\u2010587, a new diarylquinoline (DARQ), has shown promising efficacy in preclinical studies. This work aimed to describe the pharmacokinetics (PK) of TBAJ\u2010587 and its metabolites M2 and M3 after single ascending dosing in healthy volunteers and to develop a simultaneous population PK model. In addition, to explore different doses in relation to efficacy and safety and to assess the impact of loading doses on exposure levels of TBAJ\u2010587 and its metabolites.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Pharmacokinetic samples from 42 healthy volunteers following a single dose (25, 50, 100, 200, 400 or 800\u2009mg) were collected for up to Day 126. Population pharmacokinetic modelling was conducted using nonlinear mixed\u2010effects modelling in NONMEM. Simulations from final model were performed to compare against efficacy targets derived from the first\u2010in\u2010class DARQ bedaquiline and safety references based on preclinical studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results and Conclusions<\/jats:title>\n                    <jats:p>The final model simultaneously described the PK of TBAJ\u2010587, M2 and M3 well. Simulations of final model identified that all simulated doses and regimens resulted in exposures that were below the safety references. A loading dose for 2\u2009weeks resulted in initially higher concentrations, but a limited difference in exposure at 4\u00a0weeks and onwards, compared with no loading dose. A 100\u2009mg once daily dose and higher reached the efficacy targets and can be studied further in combinations in phase 2a studies. Name of trial: Evaluation of the Safety, Tolerability, PK of TBAJ\u2010587 in Healthy Adults. Registration number: NCT04890535.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bcp.70333","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T09:00:38Z","timestamp":1763542838000},"page":"1058-1068","source":"Crossref","is-referenced-by-count":4,"title":["Population pharmacokinetics of TBAJ\u2010587 and its main metabolites\u2014Evaluation of different loading dose strategies and early dose selection"],"prefix":"10.1002","volume":"92","author":[{"given":"Albin A. M.","family":"Leding","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Biosciences Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Bruinenberg","sequence":"additional","affiliation":[{"name":"TB Alliance  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Almari","family":"Conradie","sequence":"additional","affiliation":[{"name":"TB Alliance  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry","family":"Nedelman","sequence":"additional","affiliation":[{"name":"TB Alliance  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Lombardi","sequence":"additional","affiliation":[{"name":"TB Alliance  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean","family":"Hickman","sequence":"additional","affiliation":[{"name":"TB Alliance  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3424-9686","authenticated-orcid":false,"given":"Ulrika S. H.","family":"Simonsson","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biosciences Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"e_1_2_10_2_1","volume-title":"Global Tuberculosis Report 2023","author":"World Health Organization","year":"2023"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.4103\/2229\u2010516X.112228"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1901814"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2119430"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2117166"},{"key":"e_1_2_10_7_1","unstructured":"Global Alliance for TB Drug Development.Trial to evaluate the efficacy safety and tolerability of BPaMZ in drug\u2010sensitive (DS\u2010TB) adult patients and drug\u2010resistant (DR\u2010TB) adult patients.2017.https:\/\/clinicaltrials.gov\/study\/NCT03338621"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dku171"},{"key":"e_1_2_10_9_1","unstructured":"Janssen Therapeutics.SIRTURO (bedaquiline) tablets for oral use. 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