{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T02:03:00Z","timestamp":1791424980395,"version":"4.3.3"},"reference-count":31,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T00:00:00Z","timestamp":1752105600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Bedaquiline (BDQ) is a first\u2010in\u2010class diarylquinoline (DARQ) and a potent anti\u2010tuberculosis drug, vital in combating multi\u2010drug resistant tuberculosis (TB). Understanding its lung pharmacokinetics (PK) across species is crucial for effective clinical translation. This study aimed to extrapolate BDQ\u2019s lung PK from preclinical species to humans, focusing on healthy and TB\u2010infected lung tissue.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Physiologically\u2010based PK (PBPK) modelling was employed to simulate BDQ\u2019s lung distribution in various pulmonary micro\u2010compartments, including cellular lesions and caseous granulomas, using data from mice, rats and dogs. Complex interactions, such as lysosomal trapping within macrophages and anomalous diffusion within the caseum, utilising a catenary model and a time\u2010dependent rate, were incorporated into the models to accurately represent BDQ\u2019s unique PK profile.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The study revealed intricate dynamics of BDQ\u2019s lung distribution, with only free concentrations in lysosomes of macrophages surpassing the MIC of Mycobacterium tuberculosis in both mice and humans, indicating intracellular accumulation which may further explain the proven drug\u2019s efficacy. Moreover, during the course of treatment in humans, adequate drug levels were achieved near the cellular rim but penetration into the inner caseous core was predicted to be limited.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Understanding BDQ's lung PK is essential for optimising dosing strategies with new companion drugs. The findings underscore the need to characterise BDQ distribution within the caseum, as it shows extensive caseum binding. Moreover, the developed PBPK model can be applied to new promising DARQ analogues, facilitating their development as effective TB treatments.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bcp.70163","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T04:59:55Z","timestamp":1752209995000},"page":"3167-3178","source":"Crossref","is-referenced-by-count":8,"title":["Extrapolation of lung pharmacokinetics of bedaquiline across species using physiologically\u2010based pharmacokinetic modelling"],"prefix":"10.1002","volume":"91","author":[{"given":"Evangelos","family":"Karakitsios","sequence":"first","affiliation":[{"name":"Department of Pharmacy National and Kapodistrian University of Athens  Panepistimiopolis Zografou Athens Greece"},{"name":"Athena Research Center Pharma\u2010Informatics Unit  Artemidos 6 &amp; Epidavrou Marousi Greece"},{"name":"National Research Council (CNR)  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6211-1430","authenticated-orcid":false,"given":"Oscar","family":"Della Pasqua","sequence":"additional","affiliation":[{"name":"National Research Council (CNR)  Rome Italy"},{"name":"Clinical Pharmacology &amp; Therapeutics Group University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5087-4003","authenticated-orcid":false,"given":"Aristides","family":"Dokoumetzidis","sequence":"additional","affiliation":[{"name":"Department of Pharmacy National and Kapodistrian University of Athens  Panepistimiopolis Zografou Athens Greece"},{"name":"Athena Research Center Pharma\u2010Informatics Unit  Artemidos 6 &amp; Epidavrou Marousi Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,10]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01393\u201008"},{"key":"e_1_2_10_3_1","unstructured":"WHO.Global tuberculosis report2023. 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