{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T23:10:33Z","timestamp":1790205033385,"version":"4.1.0"},"reference-count":20,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T00:00:00Z","timestamp":1758672000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008021","name":"Bristol-Myers Squibb Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008021","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":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    A subcutaneous formulation of nivolumab was evaluated in the phase III study CheckMate 67T (NCT04810078). The co\u2010primary pharmacokinetic exposure endpoints, time\u2010averaged serum concentration over the first 28\u2009days (\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>avgd28<\/jats:sub>\n                    ), and steady\u2010state trough concentration (\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>minss<\/jats:sub>\n                    ) were determined through population pharmacokinetic analysis as compared to conventional non\u2010compartmental analysis (NCA). We proposed a model\u2010based approach to determine subcutaneous and intravenous nivolumab exposures in CheckMate 67T, leveraging extensive prior pharmacokinetic data across various tumor types. The robustness of this model\u2010informed drug development (MIDD) approach was assessed via clinical trial simulations. Concentration\u2013time profiles in randomly sampled patients with renal cell carcinoma receiving second\u2010line systemic therapy were simulated for subcutaneous\/intravenous nivolumab. Population pharmacokinetic parameters, sampled from the joint parameter uncertainty distribution, were applied in simulations based on the CheckMate 67T design. Two population pharmacokinetic approaches\u2014the PRIOR subroutine ($PRIOR) in NONMEM and a pooled analysis with historical nivolumab pharmacokinetic data\u2014were used to analyze the simulated data. Results were compared to NCA using intensive and conventional sampling schemes. Analyses showed that model\u2010based analysis provided more accurate area under the curve estimates than NCA. Model\u2010predicted exposure measures, including\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>avgd28<\/jats:sub>\n                    , maximum serum concentration after the first dose, and minimum serum concentration at day 28, were also consistent across both population pharmacokinetic approaches, with minimal differences in geometric means. In conclusion, both the $PRIOR and pooled population pharmacokinetic methods yielded more accurate results compared to conventional NCA. The MIDD approach was validated as a robust and feasible method to support non\u2010inferiority assessment based on clinical trial simulations.\n                  <\/jats:p>","DOI":"10.1002\/psp4.70120","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T09:21:08Z","timestamp":1758705668000},"page":"2107-2117","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Model\u2010Informed Drug Development of Subcutaneous Nivolumab: Comparison of Pharmacokinetic Analysis Methodologies Using Clinical Trial Simulation"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0814-0134","authenticated-orcid":false,"given":"Yue","family":"Zhao","sequence":"first","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Vezina","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheyi","family":"Hu","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5642-2960","authenticated-orcid":false,"given":"Anna","family":"Kondic","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhu","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2140-1455","authenticated-orcid":false,"given":"Amit","family":"Roy","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,24]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"Bristol Myers Squibb \u201cOPDIVO (Nivolumab) Package Insert \u201d2024."},{"key":"e_1_2_9_3_1","unstructured":"\u201cOPDIVO Annex I Summary of Product Characteristics \u201dMarch 2025 https:\/\/www.ema.europa.eu\/en\/documents\/product\u2010information\/opdivo\u2010epar\u2010product\u2010information_en.pdf."},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhin.2023.02.012"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3892\/mco.2016.726"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13244-019-0770-2"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(20)30070-3"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(16)00004-1"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdw685"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3747\/co.26.4220"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2021.03.047"},{"key":"e_1_2_9_12_1","unstructured":"Bristol Myers Squibb \u201cOPDIVO QVANTIGTM (Nivolumab\u2009+\u2009Hyaluronidase\u2010Nvhy) Package Insert \u201d2024 https:\/\/packageinserts.bms.com\/pi\/pi_opdivo\u2010qvantig.pdf."},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30536-2"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(14)70005-1"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-020-09695-z"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1022972420004"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3148"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-016-0177-2"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.66"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02193-17"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2024.09.002"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70120","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T09:09:27Z","timestamp":1765876167000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.70120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,24]]},"references-count":20,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/psp4.70120"],"URL":"https:\/\/doi.org\/10.1002\/psp4.70120","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,24]]},"assertion":[{"value":"2025-05-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}