{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T20:49:29Z","timestamp":1790887769025,"version":"4.1.0"},"reference-count":30,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,2,16]],"date-time":"2022-02-16T00:00:00Z","timestamp":1644969600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2018\u201005973"],"award-info":[{"award-number":["2018\u201005973"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Bedaquiline (BDQ) is recommended for treatment of multidrug\u2010resistant tuberculosis (MDR\u2010TB) for the majority of patients. Given its long terminal half\u2010life and safety concerns, such as QTc\u2010prolongation, re\u2010introducing BDQ after multiple dose interruption is not intuitive and there are currently no existing guidelines. In this simulation\u2010based study, we investigated different loading dose strategies for BDQ re\u2010introduction, taking safety and efficacy into account. Multiple scenarios of time and length of interruption as well as BDQ re\u2010introduction, including no loading dose, 1\u2010 and 2\u2010week loading doses (200\u00a0mg and 400\u00a0mg once daily), were simulated from a previously published population pharmacokinetic (PK) model describing BDQ and its main metabolite M2 PK in patients with MDR\u2010TB. The efficacy target was defined as 95.0% of the average BDQ concentration without dose interruption during standard treatment. Because M2 is the main driver for QTc\u2010prolongation, the safety limit was set to be below the maximal average M2 metabolite concentration in a standard treatment. Simulations suggest that dose interruptions between treatment weeks 3 and 72 (interruption length: 1 to 6\u00a0weeks) require a 2\u2010week loading dose of 200\u00a0mg once daily in the typical patient. If treatment was interrupted for longer than 8\u00a0weeks, a 2\u2010week loading dose (400\u00a0mg once daily) was needed to reach the proposed efficacy target, slightly exceeding the safety limit. In conclusion, we here propose a strategy for BDQ re\u2010introduction providing guidance to clinicians for safe and efficacious BDQ dosing.<\/jats:p>","DOI":"10.1002\/psp4.12768","type":"journal-article","created":{"date-parts":[[2022,2,1]],"date-time":"2022-02-01T07:35:10Z","timestamp":1643700910000},"page":"628-639","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A modeling\u2010based proposal for safe and efficacious reintroduction of bedaquiline after dose interruption: A\u00a0population pharmacokinetics study"],"prefix":"10.1002","volume":"11","author":[{"given":"Lina","family":"Keutzer","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Biosciences Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasamin","family":"Akhondipour Salehabad","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biosciences Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Davies Forsman","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases Department of Medicine Solna Karolinska Institutet  Stockholm Sweden"},{"name":"Department of Infectious Diseases Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrika\u00a0S. 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":[[2022,2,16]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"Global tuberculosis report 2021.World Health Organization;2021. License: CC BY\u2010NC\u2010SA 3.0 IGO."},{"key":"e_1_2_9_3_1","volume-title":"Module 4: treatment \u2010 drug\u2010resistant tuberculosis treatment","author":"WHO consolidated guidelines on tuberculosis","year":"2020"},{"key":"e_1_2_9_4_1","unstructured":"Janssen Pharmaceuticals Sirturo United States product insert.https:\/\/www.janssenlabels.com\/package\u2010insert\/product\u2010monograph\/prescribing\u2010information\/SIRTURO\u2010pi.pdf."},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dku171"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.2217\/fmb.10.50"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio884"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1106753"},{"key":"e_1_2_9_9_1","unstructured":"US Food and Drug Administration Center for drug evaluation and research.Application number 204384Orig1s000 Clinical Pharmacology and Biopharmaceutics review(s).http:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2012\/204384Orig1s000MedR_.pdf."},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12147"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1177\/153537020122600903"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.06126-11"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkx317"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1313865"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cix992"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jir658"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciu572"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jit352"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1086\/424849"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00445-19"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-56553-1"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0240564"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0070064"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1177\/0962280219889080"},{"key":"e_1_2_9_25_1","volume-title":"NONMEM 7.4 Users Guides","author":"Beal S","year":"1989"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/psp.2013.24"},{"key":"e_1_2_9_27_1","volume-title":"R: A. Language and Environment for Statistical Computing","author":"R Core Team","year":"2015"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0808427"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01204-07"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14199"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.113.056119"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.12768","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/psp4.12768","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.12768","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T05:24:30Z","timestamp":1692854670000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.12768"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,16]]},"references-count":30,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2022,5]]}},"alternative-id":["10.1002\/psp4.12768"],"URL":"https:\/\/doi.org\/10.1002\/psp4.12768","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,16]]},"assertion":[{"value":"2021-10-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-01-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-02-16","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}