{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T13:28:44Z","timestamp":1770384524398,"version":"3.49.0"},"reference-count":35,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T00:00:00Z","timestamp":1688083200000},"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":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Copanlisib dose selection was established under the maximum tolerated dose paradigm, and no dedicated dose\u2010finding studies have investigated copanlisib dose selection when used in combination with rituximab. In CHRONOS\u20103, copanlisib plus rituximab demonstrated significantly improved progression\u2010free survival versus placebo plus rituximab in patients with relapsed indolent non\u2010Hodgkin lymphoma (iNHL). We conducted a comprehensive investigation of copanlisib population pharmacokinetics (PopPK) from a pooled analysis of 712 patients across nine copanlisib phase I\u2013III studies and exposure\u2013response (ER) relationships for efficacy and safety from the 1\u2010year follow\u2010up of CHRONOS\u20103. PopPK analyses examined the impact of demographic, laboratory, and comedication covariates on copanlisib between\u2010patient PK variability. Individual static and time\u2010varying exposure estimates were derived to investigate exposure\u2013efficacy and exposure\u2013safety relationships. Multivariate Cox proportional hazards and logistic regression analyses examined ER relationships with consideration of predefined potentially prognostic demographic\u2010, laboratory\u2010, and\/or disease\u2010related baseline covariates. Copanlisib PK were best described by a three\u2010compartment model with first\u2010order elimination. Individual identified covariates had modest effects on copanlisib PK and were generally in line with known copanlisib disposition properties. In CHRONOS\u20103, ER analyses showed a significant relationship between time\u2010varying exposure estimates and progression\u2010free survival, and no significant exposure\u2013safety relationships. Thus, lower copanlisib doses may result in reduced efficacy but not necessarily improved safety or tolerability. These outcomes substantiate the current intermittent dosing regimen of copanlisib 60\u2009mg on days 1, 8, and 15 of a 28\u2010day cycle and support the observed clinical results of copanlisib in combination with rituximab in the iNHL population.<\/jats:p>","DOI":"10.1002\/psp4.13000","type":"journal-article","created":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T15:30:02Z","timestamp":1688139002000},"page":"1666-1686","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Copanlisib population pharmacokinetics from phase I\u2013III studies and exposure\u2013response relationships in combination with rituximab"],"prefix":"10.1002","volume":"12","author":[{"given":"Peter N.","family":"Morcos","sequence":"first","affiliation":[{"name":"Bayer HealthCare Pharmaceuticals, Inc. Whippany New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Moss","sequence":"additional","affiliation":[{"name":"BAST Inc. Limited Leicester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rupert","family":"Austin","sequence":"additional","affiliation":[{"name":"BAST Inc. Limited Leicester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florian","family":"Hiemeyer","sequence":"additional","affiliation":[{"name":"Bayer AG Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pier\u00a0Luigi","family":"Zinzani","sequence":"additional","affiliation":[{"name":"IRCCS Azienda Ospedaliero\u2010Universitaria di Bologna, Istituto di Ematologia \u201cSer\u00e0gnoli\u201d Bologna Italy"},{"name":"Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale Universit\u00e0 di Bologna Bologna Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vita","family":"Beckert","sequence":"additional","affiliation":[{"name":"Bayer AG Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lidia","family":"Mongay\u00a0Soler","sequence":"additional","affiliation":[{"name":"Bayer HealthCare Pharmaceuticals, Inc. Whippany New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barrett H.","family":"Childs","sequence":"additional","affiliation":[{"name":"Bayer HealthCare Pharmaceuticals, Inc. Whippany New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk","family":"Garmann","sequence":"additional","affiliation":[{"name":"Bayer AG Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,6,30]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"HaikeK StasikE SoujonM et al.Molecular mechanisms supporting inhibition of PI3K isoforms by copanlisib in blocking B\u2010cell signaling and tumor cell growth in diffuse large B\u2010cell lymphoma. Poster presented at: 1st American Society of Hematology Meeting on Lymphoma Biology Colorado Springs CO USA August 10\u201313 2014. doi:10.13140\/RG.2.2.24434.91847"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-12-0993-T"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-13-0611"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.12.003"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdw282"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.310"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx289"},{"key":"e_1_2_10_9_1","unstructured":"US Food and Drug Administration.ALIQOPA (copanlisib) highlights of prescribing information.2020.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2020\/209936s004lbl.pdf. Accessed January 13 2023."},{"key":"e_1_2_10_10_1","unstructured":"Taiwan Food and Drug Administration.ALIQOPA (copanlisib) Assessment Report.2022.https:\/\/www.fda.gov.tw\/tc\/includes\/GetFile.ashx?id=f637085445784753113. Accessed January 13 2023."},{"key":"e_1_2_10_11_1","unstructured":"The Israeli Drug Registry.ALIQOPA (copanlisib).2022.https:\/\/israeldrugs.health.gov.il\/#!\/medDetails\/165%2045%2035773%2000. Accessed January 13 2023."},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(21)00145-5"},{"key":"e_1_2_10_13_1","unstructured":"ZinzaniPL DreylingM Lepp\u00e4S et al.Feasibility of combining the phosphatidylinositol 3\u2010kinase (PI3K) inhibitor copanlisib with rituximab (R)\u2010based immunochemotherapy in patients (pts) with relapsed indolent non\u2010Hodgkin lymphoma (iNHL). Poster presented at: 25th Congress of the European Hematology Association (Virtual Edition) June 11\u201314 2020.https:\/\/library.ehaweb.org\/eha\/2020\/eha25th\/293660\/p.zinzani.feasibility.of.combining.the.phosphatidylinositol.3\u2010kinase.%28pi3k%29.html"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/2643-3249.LYMPHOMA22-A32"},{"key":"e_1_2_10_15_1","unstructured":"US Food and Drug Administration.Guidance for Industry: Population Pharmacokinetics.2022.https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/population\u2010pharmacokinetics. Accessed January 13 2023."},{"key":"e_1_2_10_16_1","unstructured":"European Medicines Agency.Guideline on reporting the results of population pharmacokinetic analyses.2007.https:\/\/www.ema.europa.eu\/en\/documents\/scientific\u2010guideline\/guideline\u2010reporting\u2010results\u2010population\u2010pharmacokinetic\u2010analyses_en.pdf. Accessed January 13 2023."},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-022-04417-3"},{"issue":"1","key":"e_1_2_10_18_1","first-page":"S5","article-title":"Physiologically\u2010based pharmacokinetic and clinical study to assess effects of CYP3A induction and inhibition on copanlisib PK in cancer patients","volume":"105","author":"Schlender JF","year":"2019","journal-title":"Clin Pharmacol Ther"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-19-0466"},{"key":"e_1_2_10_20_1","unstructured":"MaruyamaD FukuharaN IzutsuK et al.Phase Ib\/II study of copanlisib in Japanese patients with relapsed\/refractory indolent B\u2010cell NHL. Abstract OS1\u20107A\u20103 presented at: Japanese Society of Hematology Annual Meeting Tokyo Japan October 11\u201313 2019."},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2167"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.75.4648"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-016-3198-0"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-009-9112-5"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/69.1.239"},{"key":"e_1_2_10_26_1","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Development Core Team","year":"2016"},{"key":"e_1_2_10_27_1","unstructured":"HallowM WangW JamesDA.Package \"RxODE\": Facilities for simulating from ODE based models.2015.CRAN R Repository.https:\/\/mran.microsoft.com\/snapshot\/2016\u201010\u201014\/web\/packages\/RxODE\/RxODE.pdf. Accessed January 13 2023."},{"key":"e_1_2_10_28_1","unstructured":"TherneauTM LumleyT.Package \"survival\": Core survival analysis routines including definition of Surv objects Kaplan\u2010Meier and Aalen\u2010Johansen (multi\u2010state) curves Cox models and parametric accelerated failure time models.2018.CRAN R Repository.https:\/\/mran.microsoft.com\/snapshot\/2018\u201007\u201003\/web\/packages\/survival\/survival.pdf. Accessed January 13 2023."},{"key":"e_1_2_10_29_1","doi-asserted-by":"crossref","unstructured":"KassambaraA KosinskiM BiecekP FabianS.Package \"survminer\": Drawing survival curves using \u2018ggplot2\u2019.2017.CRAN R Repository.https:\/\/cran.microsoft.com\/snapshot\/2017\u201008\u201014\/web\/packages\/survminer\/survminer.pdf. Accessed January 13 2023.","DOI":"10.32614\/CRAN.package.survminer"},{"key":"e_1_2_10_30_1","unstructured":"US Food and Drug Administration.Updated information April 21\u201322 2022: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement. Event Materials.2022.https:\/\/www.fda.gov\/advisory\u2010committees\/advisory\u2010committee\u2010calendar\/updated\u2010information\u2010april\u201021\u201022\u20102022\u2010meeting\u2010oncologic\u2010drugs\u2010advisory\u2010committee\u2010meeting\u2010announcement. Accessed January 13 2023."},{"key":"e_1_2_10_31_1","unstructured":"US Food and Drug Administration.Final Summary Minutes of the Oncologic Drugs Advisory Committee Meeting April 21 2022.https:\/\/www.fda.gov\/media\/159332\/download. Accessed January 13 2023."},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.25711"},{"key":"e_1_2_10_33_1","unstructured":"US Food and Drug Administration.Briefing Document: Oncologic Drugs Advisory Committee Meeting April 21 2022. Phosphatidylinositol 3\u2010Kinase (PI3K) Inhibitors in Hematologic Malignancies.2022.https:\/\/www.fda.gov\/media\/157762\/download. Accessed January 13 2023."},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04685-2"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12749"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(22)00333-3"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.13000","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T12:04:08Z","timestamp":1729685048000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.13000"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,30]]},"references-count":35,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2023,11]]}},"alternative-id":["10.1002\/psp4.13000"],"URL":"https:\/\/doi.org\/10.1002\/psp4.13000","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,30]]},"assertion":[{"value":"2023-01-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}