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Recent FDA and ICH guidelines highlight a systematic, risk\u2010based approach for evaluating these interactions, emphasizing the need for a thorough mechanistic understanding of TP\u2010DIs. This study integrates the physiologically based pharmacokinetic (PBPK) model for TP (specifically interleukin\u20106, IL\u20106) with small\u2010molecule drug PBPK models to elucidate cytokine\u2010related TP\u2010DI mechanistically. The integrated model successfully predicted TP\u2010DIs across a broad range of both constant and fluctuating IL\u20106 levels, as observed in patients with rheumatoid arthritis, Crohn's disease, HIV\u2010infection, and those undergoing hip\u2010surgery or bone marrow transplantation (all simulated AUC and Cmax ratios were within a twofold error of the observed data). Constant IL\u20106 levels that would be associated with mild, moderate, and strong inhibitory interactions were estimated. The time\u2010course and extent of TP\u2010DI potential were also assessed in cytokine storm triggered by SARS\u2010CoV\u20102 infection (COVID\u201019) and T\u2010cell engager therapies (blinatumomab, mosunetuzumab, and epcoritamab). Additionally, scenarios involving concurrent CYP enzyme suppression by IL\u20106 and induction by rifampicin were assessed for the magnitude of drug interaction. By providing a robust mechanistic framework for understanding cytokine\u2013drug interactions and establishing reliable exposure\u2013response relationships, this study enhances predictive accuracy and informs human dosing strategies. It demonstrates the potential of PBPK models to improve therapeutic decision making and patient care, particularly in inflammatory conditions.<\/jats:p>","DOI":"10.1002\/cpt.3560","type":"journal-article","created":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T13:11:26Z","timestamp":1736860286000},"page":"1369-1380","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cytokine Dynamics in Action: A Mechanistic Approach to Assess Interleukin 6 Related Therapeutic Protein\u2010Drug\u2013Disease Interactions"],"prefix":"10.1002","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2418-5970","authenticated-orcid":false,"given":"Xian","family":"Pan","sequence":"first","affiliation":[{"name":"Certara Predictive Technologies Division Certara UK Limited  Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine L.","family":"Gill","sequence":"additional","affiliation":[{"name":"Certara Predictive Technologies Division Certara UK Limited  Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amita","family":"Pansari","sequence":"additional","affiliation":[{"name":"Certara Predictive Technologies Division Certara UK Limited  Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3982-734X","authenticated-orcid":false,"given":"Oliver","family":"Hatley","sequence":"additional","affiliation":[{"name":"Certara Predictive Technologies Division Certara UK Limited  Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liam","family":"Curry","sequence":"additional","affiliation":[{"name":"Certara Predictive Technologies Division Certara UK Limited  Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3443-0194","authenticated-orcid":false,"given":"Masoud","family":"Jamei","sequence":"additional","affiliation":[{"name":"Certara Predictive Technologies Division Certara UK Limited  Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iain","family":"Gardner","sequence":"additional","affiliation":[{"name":"Certara Predictive Technologies Division Certara UK Limited  Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,1,14]]},"reference":[{"key":"e_1_2_9_1_1","unstructured":"U.S. Food & Drug Administration.Drug\u2010drug interaction assessment for therapeutic proteins draft guidance for industry<www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/drug\u2010drug\u2010interaction\u2010assessment\u2010therapeutic\u2010proteins\u2010guidance\u2010industry> (2020). 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