{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T14:28:19Z","timestamp":1762957699943,"version":"build-2065373602"},"reference-count":24,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:00:00Z","timestamp":1751587200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004331","name":"Johnson and Johnson","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004331","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp;amp; Syst Pharma"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Efficacy and safety of ibrutinib 560\u2009mg once daily or placebo combined with bendamustine and rituximab (BR) were assessed in patients with mantle cell lymphoma in a randomized phase 3 study (SHINE). The analysis described explores the ibrutinib population pharmacokinetics (PK) and exposure\u2010response (E\u2010R) relationships of selected efficacy and safety endpoints. Ibrutinib PK was consistent with previous assessments, characterized by an open two\u2010compartment disposition model with sequential zero\u2010first order oral absorption after a lag time. Ibrutinib treatment was efficacious in extending PFS versus placebo (HR: 0.75; 95% CI: 0.59 to 0.96), although similar OS, CRR, and ORR were observed. PFS benefit was similar across the quartiles of ibrutinib exposure, suggesting that systemic exposures obtained provide maximal clinical response. There was no association between ibrutinib exposure and incidence of major hemorrhage, Grade \u2265\u20093 liver function test abnormalities, Grade \u2265\u20093 neutropenia, Grade \u2265\u20092 diarrhea, treatment\u2010emergent adverse events (TEAEs) leading to death, and TEAEs leading to ibrutinib dose reduction. However, the incidence of all Grade \u2265\u20093 TEAEs, all serious TEAEs, TEAEs leading to ibrutinib discontinuation, Grade \u2265\u20091 atrial fibrillation, any hemorrhage, and Grade \u2265\u20093 infection was higher in the ibrutinib than placebo arm. Of these, only atrial fibrillation and any hemorrhage increased with increasing exposure. Overall, ibrutinib 560\u2009mg, combined with BR, consistently improves PFS across the ibrutinib exposure range evaluated. According to the results of the exposure\u2010response analysis, for patients who develop specific toxicities, dose reduction according to the prescribing information may improve the ibrutinib tolerability while keeping adequate exposure to maintain efficacy.<\/jats:p>","DOI":"10.1002\/psp4.70061","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T09:45:15Z","timestamp":1751622315000},"page":"1562-1574","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Population Pharmacokinetic and Exposure\u2010Response Analyses of Ibrutinib Combined With Bendamustine and Rituximab in Patients With Mantle Cell Lymphoma"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0706-8783","authenticated-orcid":false,"given":"Per Olsson","family":"Gisleskog","sequence":"first","affiliation":[{"name":"POG Pharmacometrics  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2317-5028","authenticated-orcid":false,"given":"Bel\u00e9n","family":"Valenzuela","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology &amp; Pharmacometrics Johnson &amp; Johnson  Beerse Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicoline","family":"Treijtel","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology &amp; Pharmacometrics Johnson &amp; Johnson  Beerse Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjay","family":"Deshpande","sequence":"additional","affiliation":[{"name":"Clinical Oncology Johnson &amp; Johnson  Raritan New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Todd","family":"Henninger","sequence":"additional","affiliation":[{"name":"Clinical Oncology Johnson &amp; Johnson  Raritan New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9890-745X","authenticated-orcid":false,"given":"Juan Jos\u00e9","family":"Perez\u2010Ruixo","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology &amp; Pharmacometrics Johnson &amp; Johnson  Beerse Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,4]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mds643"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2021.39.15_suppl.7504"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61763-2"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.18.00605"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.3109\/08830185.2012.664797"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1400376"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1306220"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-018-0023-2"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2201817"},{"key":"e_1_2_12_11_1","unstructured":"\u201cFDA Clinical Phamacology and Biopharmaceutics Review(s) Ibrutinib \u201dhttps:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2013\/205552Orig1s000ClinPharmR.pdf."},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.2200"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/hematology.2020000118"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-06-095331"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.4155\/bio.15.159"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-014-2617-3"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-007-9081-1"},{"key":"e_1_2_12_18_1","unstructured":"S.Beal L.Boeckmann R.Bauer andL.Sheiner \u201cNONMEM User's Guides \u201d(1989\u20132009) (2009)."},{"volume-title":"R: A Language and Environment for Statistical Computing","year":"2016","author":"R Core Team","key":"e_1_2_12_19_1"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-025-04753-0"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2023.41.16_suppl.7538"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.14540"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2018.1554862"},{"key":"e_1_2_12_24_1","first-page":"4313","article-title":"The Impact of Front\u2010Line Ibrutinib Dose Reduction and Interruption on Outcomes in Chronic Lymphocytic Leukemia (CLL) Patients","volume":"130","author":"Rhodes J.","year":"2017","journal-title":"Blood"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.2998"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70061","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T04:03:09Z","timestamp":1760500989000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.70061"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,4]]},"references-count":24,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1002\/psp4.70061"],"URL":"https:\/\/doi.org\/10.1002\/psp4.70061","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"type":"print","value":"2163-8306"},{"type":"electronic","value":"2163-8306"}],"subject":[],"published":{"date-parts":[[2025,7,4]]},"assertion":[{"value":"2025-02-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}