{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T04:01:14Z","timestamp":1769313674844,"version":"3.49.0"},"reference-count":26,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T00:00:00Z","timestamp":1635292800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Molibresib (GSK525762) is an investigational orally bioavailable small\u2010molecule bromodomain and extraterminal (BET) protein inhibitor for the treatment of advanced solid tumors. In the first\u2010time\u2010in\u2010human BET115521 study of molibresib in patients with solid tumors, thrombocytopenia was the most frequent treatment\u2010related adverse event (AE), QT prolongation was an AE of special interest based on preclinical signals, and gastrointestinal (GI) AEs (nausea, vomiting, diarrhea, and dysgeusia) were often observed. The aims of this analysis were the following: (i) develop a population pharmacokinetic (PK)\/pharmacodynamic (PD) model capable of predicting platelet time courses in individual patients after administration of molibresib and identify covariates of clinical interest; (ii) evaluate the effects of molibresib (and\/or its two active metabolites [GSK3529246]) exposure on cardiac repolarization by applying a systematic modeling approach using high\u2010quality, intensive, PK time\u2010matched 12\u2010lead electrocardiogram measurements; (iii) evaluate the exposure\u2013response (ER) relationship between molibresib and\/or GSK3529246 exposures and the occurrence of Grade 2 or higher GI AEs. Overall, the PK\/PD model (including a maximal drug effect model and molibresib concentration) adequately described platelet counts following molibresib treatment and was used to simulate the impact of molibresib dosing on thrombocytopenia at different doses and regimens. ER analyses showed no clinically meaningful QT interval prolongation with molibresib at up to 100\u00a0mg q.d., and no strong correlation between molibresib exposure and the occurrence of Grade 2 or higher GI AEs. The models described here can aid dosing\/schedule and drug combination strategies and may support a thorough QT study waiver request for molibresib.<\/jats:p>","DOI":"10.1002\/psp4.12724","type":"journal-article","created":{"date-parts":[[2021,10,15]],"date-time":"2021-10-15T16:24:40Z","timestamp":1634315080000},"page":"556-568","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Exposure\u2013response analysis of adverse events associated with molibresib and its active metabolites in patients with solid tumors"],"prefix":"10.1002","volume":"11","author":[{"given":"Anu Shilpa","family":"Krishnatry","sequence":"first","affiliation":[{"name":"Clinical Pharmacology Modelling and Simulation GlaxoSmithKline  Collegeville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Hanze","sequence":"additional","affiliation":[{"name":"qPharmetra LLC  Nijmegen the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim","family":"Bergsma","sequence":"additional","affiliation":[{"name":"qPharmetra LLC  Nijmegen the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arindam","family":"Dhar","sequence":"additional","affiliation":[{"name":"Epigenetics Research Unit GlaxoSmithKline  Collegeville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marita","family":"Prohn","sequence":"additional","affiliation":[{"name":"qPharmetra LLC  Nijmegen the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geraldine","family":"Ferron\u2010Brady","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Modelling and Simulation GlaxoSmithKline  Collegeville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,10,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09589"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm4014407"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2016-4693"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/jncics\/pkz093"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12639"},{"issue":"4","key":"e_1_2_10_7_1","first-page":"282","article-title":"Managing thrombocytopenia associated with cancer chemotherapy","volume":"29","author":"Kuter DJ","year":"2015","journal-title":"Oncology (Williston Park)"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2002.02.140"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1006775"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12345"},{"key":"e_1_2_10_11_1","unstructured":"Food and Drug Administration.Guidance for industry. E14 clinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential for non\u2010antiarrhythmic drugs.https:\/\/www.fda.gov\/media\/71372\/download. Published 2005. 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