{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T03:05:24Z","timestamp":1789700724372,"version":"4.0.1"},"reference-count":29,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"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; Syst Pharma"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Sorfequiline is a novel diarylquinoline in development for treatment of tuberculosis. In\u00a0vitro data suggest metabolism via CYP3A4, carrying the potential for presystemic metabolism and drug\u2013drug interactions. Its major metabolite, M3, is pharmacologically active. We developed a semi\u2010mechanistic joint population pharmacokinetic model of sorfequiline and M3 in healthy volunteers. Data were pooled from two studies (CL\u2010001 and CL\u2010002). CL\u2010001 comprised a single\u2010ascending\u2010dose part (10\u2013800\u2009mg suspension fasted plus 100\u2009mg fed), a multiple\u2010ascending\u2010dose part (25, 75, or 200\u2009mg\/day for 14\u2009days, fed), and a relative bioavailability assessment including 100\u2009mg in tablet form under fed and fasted conditions. In CL\u2010002, fed participants received 200\u2009mg\/day suspension for 8\u2009days followed by 165\u2009mg\/day for 4\u2009days. Plasma concentrations were quantified using HPLC\u2013MS\/MS, and pharmacokinetic modeling and simulations were conducted in NONMEM. A three\u2010compartment disposition model for both analytes, with transit\u2010compartment absorption, adequately described the data. A fraction of the dose was assumed to be absorbed as M3 due to gut first\u2010pass metabolism. This fraction was 46% (95% CI: 41%\u201350%) in fasted and 15% (13%\u201319%) in fed participants. Overall bioavailability decreased by 46% (32%\u201361%) at fasted doses \u2265\u2009400\u2009mg. Model\u2010based simulations showed that exposures for all investigated regimens remained below safety reference values. Food reduced the fraction of sorfequiline dose absorbed as M3, likely due to limited gut first\u2010pass metabolism. The developed model provides an initial platform for future pharmacokinetic\/pharmacodynamic analyses and simulation of both analytes' exposures under drug\u2013drug interaction scenarios.<\/jats:p>","DOI":"10.1002\/psp4.70331","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T08:51:05Z","timestamp":1789116665000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Semi\u2010Mechanistic Joint Population Pharmacokinetic Modeling of the Novel Antituberculosis Drug Sorfequiline and Its Metabolite\n                    <scp>M3<\/scp>\n                    in Healthy Volunteers"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0310-6949","authenticated-orcid":false,"given":"Jose M.","family":"Calderin","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine University of Cape Town Cape Town South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry","family":"Nedelman","sequence":"additional","affiliation":[{"name":"Global Alliance for TB Drug Development New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Salinger","sequence":"additional","affiliation":[{"name":"Certara, Inc Princeton USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thanakorn","family":"Vongjarudech","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Uppsala University Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7494-079X","authenticated-orcid":false,"given":"Paolo","family":"Denti","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine University of Cape Town Cape Town South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0093-6445","authenticated-orcid":false,"given":"Elin M.","family":"Svensson","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Uppsala University Uppsala Sweden"},{"name":"Department of Pharmacy, Pharmacology and Toxicology Radboud Institute of Health Sciences, Radboud University Medical Center Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"World Health Organization \u201cGlobal tuberculosis report 2025 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