{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T18:42:00Z","timestamp":1773859320257,"version":"3.50.1"},"reference-count":17,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"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":[[2026,4]]},"abstract":"<jats:p>\n                    Abemaciclib is an oral anticancer drug indicated for treatment of HR+ HER2\u2010 breast cancer. Dose modifications due to side effects are frequent, thus drug exposures change over time as a result of altering the dose or temporarily withholding abemaciclib treatment. This limits the utility of simple exposure\u2013response assessments (such as Kaplan\u2013Meier quartile analyses) using static summary pharmacokinetic measures of drug exposure. The objective of the current work was to characterize the exposure\u2013response relationship of abemaciclib using nonlinear mixed\u2010effects modeling in 663 patients with metastatic or advanced breast cancer. A time\u2010course joint simultaneous pharmacokinetic\u2014tumor size\u2014progression\u2010free survival model accounted for changes in drug exposure due to dose reductions\/omissions and described the change in tumor size over time. The change in tumor size was a highly significant predictor of the hazard for progression\u2010free survival in a joint tumor size\u2014time to event model (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001). Interval censoring was used in the time to event model to account for wide patient visit intervals. Simulations using the combined pharmacokinetic\u2014tumor size\u2014time to event model demonstrated the adequacy of a 150\u2009mg twice daily dose in combination with fulvestrant. There was a negligible impact of dose reductions on efficacy, likely due to the shallow exposure\u2013response relationship. When analyzing survival data where the drug exposure changes significantly within an individual over time, it is important to maximize the use of available longitudinal data through simultaneous modeling of time\u2010course tumor size and survival data.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70212","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T14:02:26Z","timestamp":1769522546000},"page":"1070-1079","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Longitudinal Tumor Size and Survival Modeling for Exposure\u2013Response Analysis of Drugs with Frequent Dose Reductions: Dose Justification of Abemaciclib in Patients with Metastatic Breast Cancer"],"prefix":"10.1002","volume":"119","author":[{"given":"Emmanuel","family":"Chigutsa","sequence":"first","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6453-2749","authenticated-orcid":false,"given":"Sonya C.","family":"Chapman","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8703-5438","authenticated-orcid":false,"given":"P. Kellie","family":"Turner","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,1,27]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-023-09850-2"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13074"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12686"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12209"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.70002"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.45.0973"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-016-3116-5"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12869"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2009.64"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-014-0120-7"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.73.7585"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12544"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-03-2524"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1023249510224"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41523-024-00639-1"},{"key":"e_1_2_10_17_1","unstructured":"Min Yue A.L. Pitou C.&Chigutsa E.Exposure\u2010response modeling strategies in oncology: impact of dose reductions on interpretation of results(2023). ASCPT Annual Meeting; Atlanta GA."}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70212","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70212","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70212","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T11:43:27Z","timestamp":1773834207000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70212"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,27]]},"references-count":17,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1002\/cpt.70212"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70212","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,27]]},"assertion":[{"value":"2025-09-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}