{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T11:33:31Z","timestamp":1785929611708,"version":"3.56.0"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":48,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Medecins sans Frontieres","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Wellcome Trust and the Royal Society","award":["220587\/Z\/20\/Z"],"award-info":[{"award-number":["220587\/Z\/20\/Z"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Pretomanid is a key component of the bedaquiline, pretomanid, linezolid with or without moxifloxacin (BPaL\/M) regimen recommended for treatment of rifampicin-resistant tuberculosis (RR-TB). To support dose optimization and efficacy interpretation, we developed a pretomanid population pharmacokinetic (PK) model and evaluated exposure and probability of target attainment (PTA). Ninety-four RR-TB patients received daily oral pretomanid at 200\u00a0mg, and plasma samples were collected at multiple time points. Pretomanid concentrations were quantified using high-performance liquid chromatography-tandem mass spectrometry and PK modeling was performed using nlmixr2 in R. A one-compartment model with first-order absorption and elimination, and fat free mass allometric scaling best described the data. Typical clearance was 3.10\u00a0L\/h (32.9%CV), median AUC\u2080\u208b\u2082\u2084 was 64,000 (31,000\u2013 140,000) ng\u00b7h\/ml, and the median maximum inter-dose concentration (Cmax) was 3,000 (1,000\u2013 6,000) ng\/ml. Pretomanid MICs for\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    in the TB-PRACTECAL trial were consistently below the provisional critical concentration, with a median of 0.125\u00a0mg\/L. PK-Pharmacodynamic (PD) simulations indicated that nearly all participants achieved drug exposures exceeding %fT\u2009&gt;\u2009MIC target, consistent with the regimen\u2019s clinical efficacy across the study population. However, the AUC\/MIC target was not achieved. We developed a pretomanid population PK model and facilitated exploring robustness of PK-PD targets for PTA. Our study confirmed the clinical relevance of the time dependent index and target, but further investigation is needed to determine whether the 167 AUC\/MIC target is valid in patients or using translational pre-clinical experiments, especially within the context of combination therapy.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Trial registry<\/jats:bold>\n                    : Clinical Trials.gov, TRN: NCT04081077, Registration date: 4 September 2019.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-46217-2","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T19:26:46Z","timestamp":1774985206000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Population pharmacokinetics and target attainment of pretomanid in rifampicin-resistant tuberculosis patients"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9915-5878","authenticated-orcid":false,"given":"Bern-Thomas","family":"Nyang\u2019wa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Motta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronelle","family":"Moodliar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varvara","family":"Solodovnikova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shakira","family":"Rajaram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Rasool","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Berry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhonghui","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geraint","family":"Davies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.J.","family":"Moore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7213-4559","authenticated-orcid":false,"given":"Frank","family":"Kloprogge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"46217_CR1","unstructured":"World Health Organization. Global tuberculosis report 2025. Geneva2025."},{"key":"46217_CR2","unstructured":"WHO consolidated guidelines on tuberculosis. Module 4: Treatment (World Health Organisation, 2022)."},{"issue":"2","key":"46217_CR3","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/S2213-2600(23)00389-2","volume":"12","author":"BT Nyang\u2019wa","year":"2024","unstructured":"Nyang\u2019wa, B. T. et al. Short oral regimens for pulmonary rifampicin-resistant tuberculosis (TB-PRACTECAL): an open-label, randomised, controlled, phase 2B-3, multi-arm, multicentre, non-inferiority trial. Lancet Respir Med. 12 (2), 117\u2013128 (2024).","journal-title":"Lancet Respir Med."},{"issue":"25","key":"46217_CR4","doi-asserted-by":"publisher","first-page":"2331","DOI":"10.1056\/NEJMoa2117166","volume":"387","author":"BT Nyang\u2019wa","year":"2022","unstructured":"Nyang\u2019wa, B. T. et al. A 24-Week, All-Oral Regimen for Rifampin-Resistant Tuberculosis. N Engl. J. Med. 387 (25), 2331\u20132343 (2022).","journal-title":"N Engl. J. Med."},{"key":"46217_CR5","unstructured":"Pretomanid summary of medicinal product characteristics. US Food and Drug Administration; (2022)."},{"issue":"9","key":"46217_CR6","doi-asserted-by":"publisher","first-page":"5245","DOI":"10.1128\/AAC.03332-14","volume":"58","author":"KE Dooley","year":"2014","unstructured":"Dooley, K. E. et al. Phase I safety, pharmacokinetics, and pharmacogenetics study of the antituberculosis drug PA-824 with concomitant lopinavir-ritonavir, efavirenz, or rifampin. Antimicrob. Agents Chemother. 58 (9), 5245\u20135252 (2014).","journal-title":"Antimicrob. Agents Chemother."},{"key":"46217_CR7","doi-asserted-by":"crossref","unstructured":"Ignatius, E. H. et al. Pretomanid pharmacokinetics in the presence of rifamycins: interim results from a randomized trial among patients with tuberculosis. Antimicrob. 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Pharmacodynamics and Bactericidal Activity of Combination Regimens in Pulmonary Tuberculosis: Application to Bedaquiline-Pretomanid-Pyrazinamide. Antimicrob. Agents Chemother. 66 (12), e0089822 (2022).","journal-title":"Antimicrob. Agents Chemother."},{"issue":"11","key":"46217_CR19","doi-asserted-by":"publisher","first-page":"1585","DOI":"10.1007\/s40262-022-01163-w","volume":"61","author":"Y Zou","year":"2022","unstructured":"Zou, Y. et al. Characterizing Absorption Properties of Dispersible Pretomanid Tablets Using Population Pharmacokinetic Modelling. Clin. Pharmacokinet. 61 (11), 1585\u20131593 (2022).","journal-title":"Clin. Pharmacokinet."},{"issue":"10","key":"46217_CR20","doi-asserted-by":"publisher","first-page":"e0056522","DOI":"10.1128\/aac.00565-22","volume":"66","author":"S Howlader","year":"2022","unstructured":"Howlader, S. et al. Characterization of Clofazimine Metabolism in Human Liver Microsomal Incubation In Vitro. Antimicrob. 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The Belarus RSPCPT ethics committee and the regulator-Centre of Excellence for the Minsk site. PharmaEthics for the Don Mckenzie and Dorris Goodwin hospitals sites, University of Witwatersrand Human Research ethics committee for the Helen Joseph and King DiniZulu Hospitals sites and the South Africa Health Products Regulatory Authority.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics statement"}}],"article-number":"15255"}}