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By simultaneously binding human CD20\u2010expressing tumor cells and CD3 on T cells, glofitamab induces tumor cell lysis, in addition to T\u2010cell activation, proliferation, and cytokine release. Here, we describe physiologically\u2010based pharmacokinetic (PBPK) modeling performed to assess the impact of glofitamab\u2010associated transient increases in interleukin 6 (IL\u20106) on the pharmacokinetics of several cytochrome P450 (CYP) substrates. By refinement of a previously described IL\u20106 model and inclusion of in\u00a0vitro CYP suppression data for CYP3A4, CYP1A2, and 2C9, a PBPK model was established in Simcyp to capture the induced IL\u20106 levels seen when glofitamab is administered at the intended dose and dosing regimen. Following model qualification, the PBPK model was used to predict the potential impact of CYP suppression on exposures of various CYP probe substrates. PBPK analysis predicted that, in the worst\u2010case, the transient elevation of IL\u20106 would increase exposures of CYP3A4, CYP2C9, and CYP1A2 substrates by less than or equal to twofold. Increases for CYP3A4, CYP2C9, and CYP1A2 substrates were projected to be 1.75, 1.19, and 1.09\u2010fold following the first administration and 2.08, 1.28, and 1.49\u2010fold following repeated administrations. It is recommended that there are no restrictions on concomitant treatment with any other drugs. Consideration may be given for potential drug\u2013drug interaction during the first cycle in patients who are receiving concomitant CYP substrates with a narrow therapeutic index via monitoring for toxicity or for drug concentrations.<\/jats:p>","DOI":"10.1002\/psp4.13091","type":"journal-article","created":{"date-parts":[[2023,12,4]],"date-time":"2023-12-04T04:51:15Z","timestamp":1701665475000},"page":"396-409","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Evaluation of the potential impact on pharmacokinetics of various cytochrome <scp>P450<\/scp> substrates of increasing <scp>IL<\/scp>\u20106 levels following administration of the T\u2010cell bispecific engager glofitamab"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3333-2979","authenticated-orcid":false,"given":"Nassim","family":"Djebli","sequence":"first","affiliation":[{"name":"Roche Pharmaceutical Research and 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