{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T15:01:58Z","timestamp":1770562918469,"version":"3.49.0"},"reference-count":21,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T00:00:00Z","timestamp":1694563200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mezigdomide is a novel cereblon E3 ligase modulator (CELMoD) agent with enhanced autonomous cell\u2010killing activity in multiple myeloma (MM) cells, and promising immunomodulatory and antitumor activity in patients with MM. We developed a population pharmacokinetics (PKs) model for mezigdomide in healthy subjects (HSs), and quantified effects of high\u2010fat meal and proton pump inhibitor (PPI) on human disposition parameters. Plasma concentrations from 64 HS in two phase I clinical studies (NCT03803644 and NCT04211545) were used to develop a population PK model. The HSs received single oral doses of 0.4\u20133.2\u2009mg mezigdomide with full PK profiles collected. A two\u2010compartment linear PK model with first\u2010order absorption and lag time best described mezigdomide PK profiles in HSs. The population PK parameters of absorption rate constant, lag time, central volume of distribution, clearance, peripheral volume of distribution, and intercompartmental clearance were estimated to be 1.18\u2009h<jats:sup>\u22121<\/jats:sup> (interoccasion variability [IOV]: 65%), 0.423\u2009h (IOV: 31%), 440\u2009L (interindividual variability [IIV]: 63%), 35.1\u2009L\/h (IIV: 40%), 243\u2009L (IIV: 26%), and 36.8\u2009L\/h (IIV: 26%), respectively. High\u2010fat meal increased oral bioavailability by ~30% and PPI co\u2010administration decreased oral bioavailability by ~64%. Mezigdomide demonstrated a linear dose\u2010exposure relationship in HSs. The PK model suggests a modest effect of high\u2010fat meal, and a substantial effect of PPIs on mezigdomide oral bioavailability. This population PK model enables data integration across studies to identify important covariate effects and is being used to guide dose selection in clinical study designs for mezigdomide in patients with MM.<\/jats:p>","DOI":"10.1002\/psp4.13024","type":"journal-article","created":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T13:06:32Z","timestamp":1694696792000},"page":"1473-1484","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Model based assessment of food and acid reducing agent effects on oral absorption of mezigdomide (CC\u201092480), a novel cereblon E3 ligase modulator"],"prefix":"10.1002","volume":"12","author":[{"given":"Fan","family":"Wu","sequence":"first","affiliation":[{"name":"Bristol Myers Squibb  Princeton New\u00a0Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liangang","family":"Liu","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New\u00a0Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allison","family":"Gaudy","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New\u00a0Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaomin","family":"Wang","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New\u00a0Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leon","family":"Carayannopoulos","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New\u00a0Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Pourdehnad","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New\u00a0Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manisha","family":"Lamba","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New\u00a0Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,9,13]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b01928"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2019-124338"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2021-147812"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2022-157945"},{"key":"e_1_2_10_6_1","unstructured":"ClinicalTrials.gov identifier: NCT05519085.A study to evaluate CC\u201092480 bortezomib and dexamethasone (480Vd) versus pomalidomide bortezomib and dexamethasone (PVd) in participants with relapsed or refractory multiple myeloma (RRMM) (Successor\u20101). Updated December 9 2022.https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05519085. Accessed December 11 2022"},{"key":"e_1_2_10_7_1","unstructured":"ClinicalTrials.gov Identifier: NCT05552976.A study to evaluate CC\u201092480 in combination with carfilzomib and dexamethasone (480 Kd) versus carfilzomib and dexamethasone (Kd) in participants with relapsed or refractory multiple myeloma (SUCCESSOR\u20102) (SUCCESSOR\u20102). Updated December 9 2022.https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05552976. Accessed December 11 2022"},{"key":"e_1_2_10_8_1","unstructured":"U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Guidance for industry.Assessing the effects of food on drugs in INDs and NDAs \u2014 clinical pharmacology considerations.https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/assessing\u2010effects\u2010food\u2010drugs\u2010inds\u2010and\u2010ndas\u2010clinical\u2010pharmacology\u2010considerations. Draft published February 2019. Accessed December 11 2022"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12500"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-009-9112-5"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199937030-00003"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-019-00844-3"},{"key":"e_1_2_10_13_1","unstructured":"U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Guidance for industry.Evaluation of gastric pH\u2010dependent drug interactions with acid\u2010reducing agents: study design data analysis and clinical implications.https:\/\/www.fda.gov\/media\/144026\/download. Draft published November 2020. Accessed December 11 2022"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12513"},{"key":"e_1_2_10_15_1","volume-title":"XELODA\u00ae (capecitabine) [package insert]","author":"U.S. Food and Drug Administration","year":"2001"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12228"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2016.03.002"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2019.04.003"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2021.100231"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.356"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2014.87"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1907"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.13024","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T10:23:06Z","timestamp":1697624586000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.13024"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,13]]},"references-count":21,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2023,10]]}},"alternative-id":["10.1002\/psp4.13024"],"URL":"https:\/\/doi.org\/10.1002\/psp4.13024","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,13]]},"assertion":[{"value":"2023-03-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-24","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}