{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T18:53:47Z","timestamp":1791658427691,"version":"4.3.4"},"reference-count":39,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"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                    We present model\u2010informed selection of the recommended dose for expansion (RDE) of investigational oral ATR inhibitor tuvusertib, by integrating clinical pharmacokinetics (PK), pharmacodynamics (PD), and safety data from DDRiver Solid Tumors 301 trial Part A1 (NCT04170153). A population PK (POPPK) model was developed to characterize PK and hemoglobin (HGB) reduction after multicycle treatment was simulated using a semi\u2010mechanistic, multivariate POPPK\/PD model of reticulocyte (RET), red blood cell (RBC), and HGB dynamics. A semi\u2010mechanistic PK\u2010efficacy model characterized concentration\u2010dependent tumor growth inhibition (TGI) in\n                    <jats:italic>ARID1A<\/jats:italic>\n                    mutant xenograft models. The clinical exposure\u2010PD relationship was described for phosphorylated Ser\u2010139 residue of the histone variant H2AX (\u03b3H2AX) as a biomarker of ATR inhibition. POPPK simulations predict the average steady\u2010state concentrations to exceed phosphorylated checkpoint kinase 1 (pCHK1) IC\n                    <jats:sub>90<\/jats:sub>\n                    at 100\u2013180\u2009mg once daily (QD) and 180\u2009mg QD 2\u2009weeks (w) on\/1w off. Exposure\u2010related PD suggested target engagement of \u226580% at \u2265130\u2009mg QD. POPPK\/PD modeling showed partial HGB recovery and lower rates of Grade \u22653 anemia after multicycle treatment with 180\u2009mg QD 2w on\/1w off vs. 130\u2009mg and 180\u2009mg QD. Lesser HGB reduction was predicted for 100\u2009mg QD vs. higher QD doses. Translational modeling indicated no effect of the one\u2010week dosing break on TGI at 180\u2009mg QD. The analysis supports tuvusertib 180\u2009mg QD 2w on\/1w off as the RDE and 100\u2009mg QD as the no\u2010regret dose for clinical evaluation. This example underscores the value of integrated quantitative pharmacology analyses to inform dose selection using a totality of evidence approach.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70029","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T14:10:48Z","timestamp":1755785448000},"page":"618-628","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Integrated Population Pharmacokinetic, Pharmacodynamic, and Safety Analyses to Inform Dosage Selection in the Clinical Development of the\n                    <scp>ATR<\/scp>\n                    Inhibitor Tuvusertib"],"prefix":"10.1002","volume":"119","author":[{"given":"Jatinder Kaur","family":"Mukker","sequence":"first","affiliation":[{"name":"EMD Serono  Billerica Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3567-7903","authenticated-orcid":false,"given":"Paul Matthias","family":"Diderichsen","sequence":"additional","affiliation":[{"name":"Certara USA, Inc.  Radnor Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farina","family":"Hellmann","sequence":"additional","affiliation":[{"name":"Certara USA, Inc.  Radnor Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2154-3309","authenticated-orcid":false,"given":"Timothy A.","family":"Yap","sequence":"additional","affiliation":[{"name":"Department of Investigational Cancer Therapeutics University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Plummer","sequence":"additional","affiliation":[{"name":"Newcastle University and Northern Centre for Cancer Care Newcastle Hospitals NHS Trust  Newcastle Upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony W.","family":"Tolcher","sequence":"additional","affiliation":[{"name":"Clinical Research, New Experimental Therapeutics (NEXT)  San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johann S.","family":"de Bono","sequence":"additional","affiliation":[{"name":"Division of Clinical Studies Royal Marsden Hospital  Sutton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2755-6597","authenticated-orcid":false,"given":"Ioannis","family":"Gounaris","sequence":"additional","affiliation":[{"name":"Merck Serono Ltd., Feltham, UK, an affiliate of Merck KGaA  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoltan","family":"Szucs","sequence":"additional","affiliation":[{"name":"Merck Serono Ltd., Feltham, UK, an affiliate of Merck KGaA  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"The Healthcare Business of Merck KGaA  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1100-6806","authenticated-orcid":false,"given":"Irina","family":"Kareva","sequence":"additional","affiliation":[{"name":"EMD Serono  Billerica Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayaprakasam","family":"Bolleddula","sequence":"additional","affiliation":[{"name":"EMD Serono  Billerica Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annick","family":"Seithel\u2010Keuth","sequence":"additional","affiliation":[{"name":"The Healthcare Business of Merck KGaA  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Locatelli","sequence":"additional","affiliation":[{"name":"The Healthcare Business of Merck KGaA  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Enderlin","sequence":"additional","affiliation":[{"name":"The Healthcare Business of Merck KGaA  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7750-8892","authenticated-orcid":false,"given":"Christine","family":"Hicking","sequence":"additional","affiliation":[{"name":"The Healthcare Business of Merck KGaA  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anup","family":"Zutshi","sequence":"additional","affiliation":[{"name":"EMD Serono  Billerica Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3149-8486","authenticated-orcid":false,"given":"Wei","family":"Gao","sequence":"additional","affiliation":[{"name":"EMD Serono  Billerica Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0543-7984","authenticated-orcid":false,"given":"Rainer","family":"Strotmann","sequence":"additional","affiliation":[{"name":"The Healthcare Business of Merck KGaA  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Benincosa","sequence":"additional","affiliation":[{"name":"EMD Serono  Billerica Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4039-9813","authenticated-orcid":false,"given":"Karthik","family":"Venkatakrishnan","sequence":"additional","affiliation":[{"name":"EMD Serono  Billerica Massachusetts 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combined with niraparib or lartesertib in participants with epithelial ovarian cancer (DDRiver EOC 302)<https:\/\/clinicaltrials.gov\/study\/NCT06433219?term=NCT06433219&rank=1>. Accessed December 09 2024."},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-024-00863-5"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02399-0"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2023.09.1866"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2022.40.16_suppl.3111"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.12793\/tcp.2022.30.e9"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp2109826"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3298"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3350"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2416"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.70050"},{"key":"e_1_2_11_24_1","volume-title":"Holistic integration of population pharmacokinetics, pharmacodynamics, and safety to define the recommended dose for expansion of ATR inhibitor M1774: an illustration of model\u2010informed early oncology drug development","author":"Mukker J.K.","year":"2023"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12251"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2021.102287"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-03-2524"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.926"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1023573429626"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2621"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12345"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-010-9249-2"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-010-9437-z"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3246"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c01917"},{"key":"e_1_2_11_36_1","unstructured":"Liu D.et al.A phase I study of ATR inhibitor tuvusertib (DDRiver solid tumors 301): dose confirmation in a Chinese cohort. Chinese Society of Clinical Oncology (CSCO)<http:\/\/meeting.csco.org.cn\/pdf\/web\/viewer.html?file=%2FUpload%2FPeriodical%2F20241008032522.pdf> (2024). Accessed December 11 2024."},{"key":"e_1_2_11_37_1","unstructured":"Yamamoto N.et al.A phase I study of ATR inhibitor tuvusertib in patients with solid tumours (DDRiver Solid Tumours 301): dose confirmation in japanese patients. Presented at the Japanese Society of Medical Oncology (JSMO)(2024) (Poster Presentation)."},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2024.102683"},{"key":"e_1_2_11_39_1","unstructured":"Clinicaltrials.gov.M1774 in Participants With Metastatic or Locally Advanced Unresectable Solid Tumors (DDRiver Solid Tumors 301)<https:\/\/www.clinicaltrials.gov\/study\/NCT04170153>. Accessed December 09 2024."}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70029","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70029","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70029","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T07:10:09Z","timestamp":1771312209000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70029"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,21]]},"references-count":39,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1002\/cpt.70029"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70029","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,21]]},"assertion":[{"value":"2024-12-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}