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In this study, a physiologically\u2010based pharmacokinetic (PBPK) model was developed to assess CYPs mediated therapeutic protein drug interactions (TP\u2010DIs) in patients with immune\u2010mediated inflammatory diseases (IMIDs) with elevated systemic IL\u20106 levels when treated by anti\u2010IL\u20106 therapies. Literature data of IL\u20106 levels in various diseases were incorporated in SimCYP to construct respective virtual patient populations. The modulation effects of systemic IL\u20106 level and local IL\u20106 level in the gastrointestinal tract (GI) on CYPs activities were assessed. Upon blockade of the IL\u20106 signaling pathway by an anti\u2010IL\u20106 treatment, the area under plasma concentration versus time curves (AUCs) of S\u2010warfarin, omeprazole, and midazolam were predicted to decrease by up to 40%, 42%, and 46%, respectively. In patients with Crohn\u2019s disease and ulcerative colitis treated with an anti\u2010IL\u20106 therapy, the lowering of the elevated IL\u20106 levels in the local GI tissue were predicted to result in further decreases in AUCs of those CYP substrates. The propensity of TP\u2010DIs under comorbidity conditions, such as in patients with cancer with IMID, were also explored. With further validation with relevant clinical data, this PBPK model may provide an in silico way to quantify the magnitude of potential TP\u2010DI in patients with elevated IL\u20106 levels when an anti\u2010IL\u20106 therapeutic is used with concomitant small\u2010molecule drugs. This model may be further adapted to evaluate the CYP modulation effect by other therapeutic modalities, which would significantly alter levels of proinflammatory cytokines during the treatment period.<\/jats:p>","DOI":"10.1111\/cts.13164","type":"journal-article","created":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T02:59:02Z","timestamp":1632797942000},"page":"464-476","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Utilization of physiologically\u2010based pharmacokinetic model to assess disease\u2010mediated therapeutic protein\u2010disease\u2010drug interaction in immune\u2010mediated inflammatory diseases"],"prefix":"10.1111","volume":"15","author":[{"given":"Lujing","family":"Wang","sequence":"first","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Janssen Research &amp; Development, LLC Spring House Pennsylvania USA"},{"name":"Department of Pharmaceutics Ernest Mario School of Pharmacy, Rutgers The State University of New Jersey Piscataway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6027-7955","authenticated-orcid":false,"given":"Yang","family":"Chen","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Janssen Research &amp; Development, LLC Spring House Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wangda","family":"Zhou","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Janssen Research &amp; Development, LLC Spring House Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Miao","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Janssen Research &amp; Development, LLC Spring House Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honghui","family":"Zhou","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Janssen Research &amp; Development, LLC Spring House Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,10,20]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.113.205369"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2008.302"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/1520-6017(200105)90:5<638::AID-JPS1020>3.0.CO;2-L"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-019-00810-z"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2009.05.014"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.113.052225"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.111.038679"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.114.059246"},{"key":"e_1_2_9_10_1","first-page":"707","article-title":"Cytokines down\u2010regulate expression of major cytochrome P\u2010450 enzymes in adult human hepatocytes in primary culture","volume":"44","author":"Abdel\u2010Razzak Z","year":"1993","journal-title":"Mol Pharmacol"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.561"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1177\/0961203314530793"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI31871"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-1993"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1385\/CRIAI:28:3:187"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.128"},{"key":"e_1_2_9_17_1","volume-title":"The trick of treating cancer in autoimmune diseases","author":"Arenschield L","year":"2019"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-7843.2009.00488.x"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425255.3.2.235"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600721003"},{"key":"e_1_2_9_21_1","unstructured":"U.S. Food & Drug Administration.Drug\u2010Drug Interaction Assessment for Therapeutic Proteins Guidance for Industry; Aug. 2020"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2013.79"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-016-9890-5"},{"key":"e_1_2_9_24_1","unstructured":"U.S. Food & Drug Administration.Clinical Drug Interaction Studies\u2014Cytochrome P450 Enzyme\u2010 and Transporter\u2010Mediated Drug Interactions Guidance for Industry. 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