{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T20:05:07Z","timestamp":1792267507307,"version":"4.4.0"},"reference-count":26,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T00:00:00Z","timestamp":1702857600000},"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":["Clinical Translational Sci"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>PF\u201006835919, a ketohexokinase inhibitor, presented as an inducer of cytochrome P450 3A4 (CYP3A4) in\u00a0vitro (human primary hepatocytes), and static mechanistic modeling exercises predicted significant induction in\u00a0vivo (oral midazolam area under the plasma concentration\u2010time curve [AUC] ratio [AUCR]\u2009=\u20090.23\u20130.79). Therefore, a drug\u2013drug interaction study was conducted to evaluate the effect of multiple doses of PF\u201006835919 (300\u2009mg once daily\u2009\u00d7\u200910\u2009days; <jats:italic>N<\/jats:italic>\u2009=\u200910 healthy participants) on the pharmacokinetics of a single oral midazolam 7.5\u2009mg dose. The adjusted geometric means for midazolam AUC and its maximal plasma concentration were similar following co\u2010administration with PF\u201006835919 (vs. midazolam administration alone), with ratios of the adjusted geometric means (90% confidence interval [CI]) of 97.6% (90% CI: 79.9%\u2013119%) and 98.9% (90% CI: 76.4%\u2013128%), respectively, suggesting there was minimal effect of PF\u201006835919 on midazolam pharmacokinetics. Lack of CYP3A4 induction was confirmed after the preparation of subject plasma\u2010derived small extracellular vesicles (sEVs) and conducting proteomic and activity (midazolam 1\u2032\u2010hydroxylase) analysis. Consistent with the midazolam AUCR observed, the CYP3A4 protein expression fold\u2010induction (geometric mean, 90% CI) was low in liver (0.9, 90% CI: 0.7\u20131.2) and non\u2010liver (0.9, 90% CI: 0.7\u20101.2) sEVs (predicted AUCR\u2009=\u20091.0, 90% CI: 0.9\u20131.2). Likewise, minimal induction of CYP3A4 activity (geometric mean, 90% CI) in both liver (1.1, 90% CI: 0.9\u20131.3) and non\u2010liver (0.9, 90% CI: 0.5\u20101.5) sEVs was evident (predicted AUCR\u2009=\u20090.9, 90% CI: 0.6\u20101.4). The results showcase the integrated use of an oral CYP3A probe (midazolam) and plasma\u2010derived sEVs to assess a drug candidate as inducer.<\/jats:p>","DOI":"10.1111\/cts.13644","type":"journal-article","created":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T15:01:48Z","timestamp":1702911708000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Study of the ketohexokinase inhibitor <scp>PF<\/scp>\u201006835919 as a clinical cytochrome <scp>P450 3A<\/scp> inducer: Integrated use of oral midazolam and liquid biopsy"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4051-6680","authenticated-orcid":false,"given":"Ruolun","family":"Qiu","sequence":"first","affiliation":[{"name":"Pfizer Inc  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari","family":"Fonseca","sequence":"additional","affiliation":[{"name":"Pfizer Inc  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Bergman","sequence":"additional","affiliation":[{"name":"Pfizer Inc  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Lin","sequence":"additional","affiliation":[{"name":"Pfizer Inc  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5843-7959","authenticated-orcid":false,"given":"David","family":"Tess","sequence":"additional","affiliation":[{"name":"Pfizer Inc  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3303-1666","authenticated-orcid":false,"given":"Lauren","family":"Newman","sequence":"additional","affiliation":[{"name":"Flinders University  Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alia","family":"Fahmy","sequence":"additional","affiliation":[{"name":"Flinders University  Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4566-5036","authenticated-orcid":false,"given":"Zivile","family":"Useckaite","sequence":"additional","affiliation":[{"name":"Flinders University  Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8946-3954","authenticated-orcid":false,"given":"Andrew","family":"Rowland","sequence":"additional","affiliation":[{"name":"Flinders University  Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoli","family":"Vourvahis","sequence":"additional","affiliation":[{"name":"Pfizer Inc  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Pfizer Inc  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,12,18]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23535"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2009.05.033"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.292.8.927"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI96702"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2020.100217"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c00944"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2021.101196"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.medj.2021.04.007"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.122.000953"},{"key":"e_1_2_11_11_1","unstructured":"U.S. Food & Drug Administration.In vitro drug interaction studies \u2014 cytochrome P450 enzyme\u2010 and transporter\u2010mediated drug interactions guidance for industry.2020. 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