{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:24:14Z","timestamp":1791930254087,"version":"4.3.4"},"reference-count":50,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2023,7,16]],"date-time":"2023-07-16T00:00:00Z","timestamp":1689465600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Tuberculosis (TB) is a leading cause of mortality attributed to an infectious agent. TB primarily targets the lungs, but in about 16% cases can affect other organs as well, giving rise to extrapulmonary TB (EPTB). However, an optimal regimen for EPTB treatment is not defined. Although the recommended treatment for most forms of EPTB is the same as pulmonary TB, the pharmacokinetics of EPTB therapy are not as well studied. To address this gap, we formulate a whole\u2010body physiologically\u2010based pharmacokinetic (PBPK) model for EPTB that for the first time includes the ability to simulate drug concentrations in the pleura and lymph node, the most commonly affected sites of EPTB. Using this model, we estimate the time\u2010dependent concentrations, at potential EPTB infection sites, of the following four first\u2010line anti\u2010TB drugs: rifampicin, ethambutol, isoniazid, and pyrazinamide. We use reported plasma concentration kinetics data to estimate model parameters for each drug and validate our model using reported concentration data not used for model formulation or parameter estimation. Model predictions match the validation data, and reported pharmacokinetic parameters (maximum plasma concentration, time to reach maximum concentration) for the drugs. The model also predicts ethambutol, isoniazid, and pyrazinamide concentrations in the pleura that match reported experimental values from an independent study. For each drug, the predicted drug concentrations at EPTB sites are compared with their critical concentration. Simulations suggest that although rifampicin and isoniazid concentrations are greater than critical concentration values at most EPTB sites, the concentrations of ethambutol and pyrazinamide are lower than their critical concentrations at most EPTB sites.<\/jats:p>","DOI":"10.1002\/psp4.13008","type":"journal-article","created":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T01:29:50Z","timestamp":1689038990000},"page":"1274-1284","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A\n                    <scp>physiologically\u2010based<\/scp>\n                    pharmacokinetic model for tuberculosis drug disposition at extrapulmonary sites"],"prefix":"10.1002","volume":"12","author":[{"given":"Aparna","family":"Ramachandran","sequence":"first","affiliation":[{"name":"Chemical Engineering and Process Development Division Council of Scientific and Industrial Research\u2010National Chemical Laboratory  Pune India"},{"name":"Academy of Scientific and Innovative Research, Council Of Scientific And Industrial Research\u2013Human Resource Development Centre Campus  Ghaziabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chetan J.","family":"Gadgil","sequence":"additional","affiliation":[{"name":"Chemical Engineering and Process Development Division Council of Scientific and Industrial Research\u2010National Chemical Laboratory  Pune India"},{"name":"Academy of Scientific and Innovative Research, Council Of Scientific And Industrial Research\u2013Human Resource Development Centre Campus  Ghaziabad India"},{"name":"Council of Scientific and Industrial Research\u2010Institute of Genomics and Integrative Biology  Delhi India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,7,16]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.76"},{"key":"e_1_2_10_3_1","unstructured":"World Health Organization.Global tuberculosis report 2020.2020Published online."},{"key":"e_1_2_10_4_1","unstructured":"World Health Organization.Global tuberculosis report 2022. 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