{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:51:31Z","timestamp":1792068691408,"version":"4.4.0"},"reference-count":32,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp;amp; Syst Pharma"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Tuberculosis (TB) treatment requires long\u2010term multidrug regimens where dosing, efficacy, and safety optimization remain challenging. This tutorial establishes an integrated, open\u2010source, modular framework connecting high\u2010throughput PBPK (HT\u2010PBPK) simulations, mechanistic PBPK models, pharmacodynamic endpoints, and safety predictions for anti\u2010TB drugs. Using the Open Systems Pharmacology Suite and ESQhtpbpk (R package), physicochemical parameters were obtained from literature, with QSAR\u2010predicted values supplementing missing experimental data to generate generic PBPK models. Mechanistic models were parameterized for moxidectin, isoniazid, moxifloxacin, bedaquiline, and rifampicin. A quantitative TB disease model of host\u2010pathogen dynamics and PK\u2010PD interactions was integrated to assess efficacy. A cardiac electrophysiology model incorporating ion channel inhibition data was coupled with PBPK predictions for moxifloxacin and bedaquiline. The HT\u2010PBPK framework automated virtual studies across compounds and dosing regimens. Mechanistic models reproduced systemic and local disposition within two\u2010fold of the observed data. The TB disease model predicted treatment response across exposure scenarios. The cardiac module captured the dose\u2010QTc relationship for moxifloxacin and identified metabolite\u2010driven QTc prolongation with bedaquiline, consistent with clinical observations. This open\u2010source, modular framework spans compound screening, mechanistic PK, efficacy, and cardiotoxicity, providing a reproducible tool to support TB drug development, guide dose selection, and inform regulatory decisions.<\/jats:p>","DOI":"10.1002\/psp4.70347","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:15:42Z","timestamp":1791274542000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Application of an Open\u2010Source Modular Framework for Pharmacokinetic, Pharmacodynamic, and Safety Simulations to Anti\u2010Tuberculosis Drugs"],"prefix":"10.1002","volume":"15","author":[{"given":"Marco","family":"Siccardi","sequence":"first","affiliation":[{"name":"ESQlabs GmbH  Saterland Germany"},{"name":"University of Liverpool  Liverpool 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