{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T16:50:23Z","timestamp":1793638223496,"version":"4.5.1"},"reference-count":32,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100008021","name":"Bristol-Myers Squibb Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008021","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:p>\n                    Mezigdomide (MEZI) is an oral, highly potent CELMoD\u2122 agent with promising antitumor and immune\u2010stimulatory activity, optimized for Aiolos and Ikaros degradation. Preclinical evidence suggests MEZI is primarily metabolized by cytochrome P450 (CYP) 3A4\/5 and has the potential to inhibit efflux transporters P\u2010glycoprotein (P\u2010gp) and breast cancer resistance protein (BCRP)\n                    <jats:italic>in vitro<\/jats:italic>\n                    . To predict the magnitude of enzyme\u2010 and transporter\u2010mediated drug\u2013drug interactions (DDI) and inform clinical study design, a physiologically based pharmacokinetic (PBPK) model was developed. A PBPK\u2010informed Phase I clinical DDI study was conducted that evaluated MEZI as an object of CYP3A induction (rifampin) and inhibition (itraconazole) and as a precipitant of transporter\u2010mediated interactions (digoxin and rosuvastatin). PBPK modeling predicted substantial interactions with strong and moderate CYP3A modulators, which informed a unique dose selection strategy, PK sampling time, and washout period. Clinical results confirmed reductions in MEZI exposure with rifampin (AUC reduced 93\u201395%) and increases with itraconazole (~14\u2010fold for dose normalized AUC). MEZI was well\u2010tolerated despite these changes in exposure. Additionally, coadministration of MEZI with P\u2010gp and BCRP substrates, digoxin and rosuvastatin, showed no clinically meaningful changes in substrate plasma PK, indicating a low likelihood of significant transporter\u2010mediated DDIs. The prospective PBPK model was refined with clinical data, improving predictions and supporting simulations for moderate\/weak CYP3A modulators. This iterative \u201clearn\u2010confirm\u201d approach underscores the utility of PBPK modeling in optimizing clinical trial design, ensuring participant safety, and anticipating DDI risks. The findings support MEZI\u2019s clinical development with informed dosing strategies, particularly for coadministration with CYP3A modulators.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70082","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T05:23:52Z","timestamp":1759901032000},"page":"641-650","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Application of Physiologically Based Pharmacokinetic Modeling to Inform Dose Selection of Mezigdomide in a Phase I Drug\u2013Drug Interaction Study"],"prefix":"10.1002","volume":"119","author":[{"given":"Joseph","family":"Burnett","sequence":"first","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7255-8500","authenticated-orcid":false,"given":"Caroline","family":"Sychterz","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Katz","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faisal","family":"Shakeel","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Silva","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wencong","family":"Chen","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditi","family":"Shahane","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomin","family":"Wang","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manisha","family":"Lamba","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7677-5927","authenticated-orcid":false,"given":"Allison","family":"Gaudy","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,7]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1402551"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.72.6679"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-11-538835"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(13)70380-2"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(09)70284-0"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/bcj.2015.66"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-05-356063"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1177319"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2011.03.006"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b01928"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13024"},{"issue":"1","key":"e_1_2_9_12_1","first-page":"S160","article-title":"Application of PBPK modeling and simulation for regulatory decision making and its impact on US prescribing information: an update on the 2018\u20102019 submissions to the US FDA\u2019s Office of Clinical Pharmacology","volume":"60","author":"Zhang X.","year":"2020","journal-title":"J. Clin. Pharmacol."},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdd.2257"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2643"},{"key":"e_1_2_9_15_1","first-page":"20180042","article-title":"Drug\u2010drug interaction (DDI) assessments of ruxolitinib, a dual substrate of CYP3A4 and CYP2C9, using a verified physiologically based pharmacokinetic (PBPK) model to support regulatory submissions","volume":"34","author":"Umehara K.","year":"2019","journal-title":"Drug Metab. Pers. Ther."},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3005"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdd.2272"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12234"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.110.036103"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.10005"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.20073"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.20322"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.20502"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2024-198408"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12646"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270002042012008"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40495-016-0059-9"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.114.058040"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199937060-00004"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389200215666141125121511"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00877-1"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1693"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70082","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70082","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70082","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T07:10:08Z","timestamp":1771312208000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70082"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,7]]},"references-count":32,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1002\/cpt.70082"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70082","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,7]]},"assertion":[{"value":"2025-05-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}