{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T08:40:03Z","timestamp":1750063203103,"version":"3.41.0"},"reference-count":23,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T00:00:00Z","timestamp":1747008000000},"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":[[2025,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Ritlecitinib is a kinase inhibitor drug recently approved for the treatment of alopecia areata (AA) in both adults and adolescents based on a single, combined Phase 2b\/3 study. Various QD doses with and without a loading dose have been evaluated in the pivotal Phase 2b\/3 study. Therefore, characterization of the ritlecitinib safety profile becomes important to help inform the dose selection within the single Phase 2b\/3 trial in conjunction with efficacy analysis. The purpose of this study is to characterize the safety profile of ritlecitinib with comprehensive exposure\u2010response (ER) analyses. The concentration\u2010QTc model was developed using a scientific white paper model, indicating no evidence of ritlecitinib\u2010induced QTc prolongation. The semi\u2010mechanistic PK\/PD model well described the longitudinal profile of lymphocytes, indicating ritlecitinib\u2010induced decrease in lymphocytes was marginal and the incidence of Grade 3\/4 lymphopenia was predicted to be small across the investigated dose range except for a slight increase in the loading dose regimen. The ritlecitinib\u2010dependent increase in the incidence of infections and rash was successfully described by a Poisson regression model using time\u2010weighted average concentration as an exposure metric, indicating that the dose\u2010dependent increase in the incidence of AEs is not dose\u2010proportionally large in the investigated dose range. Covariate analysis within each model indicated that the safety ER relationship of ritlecitinib is similar across all the patient subgroups and no unique safety risks associated with ritlecitinib are anticipated in adolescent patients. Therefore, this comprehensive safety ER analysis supported the selection of the ritlecitinib 50\u2009mg non\u2010loading dose regimen for AA patients including both adults and adolescents.<\/jats:p>","DOI":"10.1002\/psp4.70030","type":"journal-article","created":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T12:39:19Z","timestamp":1747053559000},"page":"1108-1118","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive Safety Exposure\u2010Response Analysis to Support Ritlecitinib Dose Selection"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0365-4467","authenticated-orcid":false,"given":"Yeamin","family":"Huh","sequence":"first","affiliation":[{"name":"Pfizer Research and Development Pfizer Inc  Groton Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4051-6680","authenticated-orcid":false,"given":"Ruolun","family":"Qiu","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development Pfizer Inc  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5802-0539","authenticated-orcid":false,"given":"John","family":"Prybylski","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development Pfizer Inc  Groton Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3302-8742","authenticated-orcid":false,"given":"Jessica","family":"Wojciechowski","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development Pfizer Inc  Groton Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2351-2090","authenticated-orcid":false,"given":"Yuchen","family":"Wang","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development Pfizer Inc  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9019-0789","authenticated-orcid":false,"given":"Vivek S.","family":"Purohit","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development Pfizer Inc  Groton Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,5,12]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2019.08.032"},{"issue":"4","key":"e_1_2_9_3_1","article-title":"The Efficacy and Adverse Effects of Corticosteroid Pulse Therapy in Alopecia Areata: A Review Article","volume":"13","author":"Rastaghi F.","year":"2023","journal-title":"Dermatology Practical & Conceptual"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jisp.2017.10.003"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2018.01.048"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)00222-2"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2110343"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2024.06.097"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-024-01347-6"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-017-9558-5"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2002.02.140"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262\u2010023\u201001318\u20103"},{"key":"e_1_2_9_13_1","unstructured":"\u201cMulti\u2010Disciplinary Review and Evaluation for NDA 215830 Litfulo (Ritlecitinib) Capsule \u201d2023 https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2023\/215830Orig1s000MultidisciplineR.pdf."},{"key":"e_1_2_9_14_1","unstructured":"\u201cE14 Clinical Evaluation of QT\/QTc Interval Prolongation and Proarrhythmic Potential for Non\u2010Antiarrhythmic Drugs\u2014Questions and Answers (R3) \u201d2017 https:\/\/www.fda.gov\/media\/71379\/download."},{"key":"e_1_2_9_15_1","unstructured":"LITFULO U.S. Label.2023 https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2023\/215830s000lbl.pdf."},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2015.132142"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2017.51"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.15334"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-021-06003-z"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13074"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)01231-X"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1201\/9781420035285"},{"key":"e_1_2_9_23_1","unstructured":"\u201cICH Guidance E11A Pediatric Extrapolation \u201d2022 https:\/\/www.fda.gov\/media\/161190\/download."},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/geronj\/33.2.213"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70030","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T08:07:57Z","timestamp":1750061277000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.70030"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,12]]},"references-count":23,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,6]]}},"alternative-id":["10.1002\/psp4.70030"],"URL":"https:\/\/doi.org\/10.1002\/psp4.70030","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"type":"print","value":"2163-8306"},{"type":"electronic","value":"2163-8306"}],"subject":[],"published":{"date-parts":[[2025,5,12]]},"assertion":[{"value":"2024-12-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}