{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T14:04:27Z","timestamp":1787321067780,"version":"build-2736575974"},"reference-count":38,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T00:00:00Z","timestamp":1750291200000},"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":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    In this study, we investigated the pharmacokinetic\/pharmacodynamic (PK\/PD) relationship of dupilumab as an add\u2010on therapy in the intent\u2010to\u2010treat (ITT) uncontrolled moderate\u2010to\u2010severe asthma population and identified the factors significantly contributing to variability in forced expiratory volume in 1\u2009second; (FEV\n                    <jats:sub>1<\/jats:sub>\n                    ). A semi\u2010mechanistic population PK\/PD model was developed using data from two placebo\u2010controlled pivotal studies in 2654 adult and adolescent patients (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009794 treated with placebo;\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20091860 treated with dupilumab 200\u2009mg [400\u2010mg loading dose] or 300\u2009mg [600\u2010mg loading dose] administered subcutaneously every 2 [Q2W] or 4\u2009weeks [Q4W]). Treatment effect was described using a dupilumab concentration\u2010dependent direct\u2010response\n                    <jats:italic>E<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    model, and placebo effect was described using an empirical time\u2010dependent function. Demographic variables, baseline disease characteristics, type\u20102 inflammation biomarkers, and immunogenicity were tested as covariates using the stepwise forward selection and backward elimination method. Baseline type\u20102 inflammation biomarkers (fractional exhaled nitric oxide [FeNO] level and blood eosinophil [EOS] count) were found to be significant covariates for FEV\n                    <jats:sub>1<\/jats:sub>\n                    , with greater efficacy in patients with elevated biomarker levels. None of the other tested covariates, including age (12\u201387\u2009years), had a significant impact on FEV\n                    <jats:sub>1<\/jats:sub>\n                    . The PK\/PD model predicted near\u2010maximum FEV\n                    <jats:sub>1<\/jats:sub>\n                    response (0.1\u2009L) over a dose of dupilumab. 200\u2013300\u2009mg Q2W in patients with moderate\u2010to\u2010severe asthma.\n                  <\/jats:p>","DOI":"10.1002\/psp4.70057","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T08:28:48Z","timestamp":1750321728000},"page":"1370-1380","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Semi\u2010Mechanistic Population Pharmacokinetic\/Pharmacodynamic (\n                    <scp>PK<\/scp>\n                    \/\n                    <scp>PD<\/scp>\n                    ) Modeling of Dupilumab on Pre\u2010Bronchodilator Forced Expiratory Volume in 1\u2009Second (\n                    <scp>\n                      FEV\n                      <sub>1<\/sub>\n                    <\/scp>\n                    ) in Uncontrolled Moderate\u2010To\u2010Severe Asthma"],"prefix":"10.1002","volume":"14","author":[{"given":"Li","family":"Zhang","sequence":"first","affiliation":[{"name":"Sanofi, Bridgewater  New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Davis","sequence":"additional","affiliation":[{"name":"Regeneron Pharmaceuticals, Inc.  Tarrytown New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanaja","family":"Kanamaluru","sequence":"additional","affiliation":[{"name":"Sanofi, Bridgewater  New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Xu","sequence":"additional","affiliation":[{"name":"Sanofi, Bridgewater  New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,19]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/alr.21609"},{"key":"e_1_2_10_3_1","unstructured":"Asthma GIf Global Strategy for Asthma Management and Prevention(2024) https:\/\/ginasthma.org\/."},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40248-016-0073-0"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0804579"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.02730-2021"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2017.05.001"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200401-033OC"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2006.03.031"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3109\/02770900903518835"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)30307-5"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)31324-1"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(15)00042-9"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)31322-8"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-154-9-201105030-00002"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2011.04.039"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1403290"},{"key":"e_1_2_10_18_1","volume-title":"TEZSPIR (tezepelumab\u2010ekko) U.S. Food and Drug Administration Priscribing Information","year":"2023"},{"key":"e_1_2_10_19_1","volume-title":"Xolair (Omalizumab) 150 mg Solution for Injection\u2014Summary of Product Characteristics","year":"2024"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2016.03.018"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(16)30031-5"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2015.05.008"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4624"},{"key":"e_1_2_10_24_1","volume-title":"Dupixent (dupilumab) [Package Insert]","year":"2024"},{"key":"e_1_2_10_25_1","volume-title":"Dupixent (Dupilumab) Summary of Product Characteristics","year":"2022"},{"key":"e_1_2_10_26_1","volume-title":"Dupixent (Dupilumab) Japan PMDA Prescribing Information","year":"2024"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arbr.2018.04.003"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/psp.2012.4"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1804092"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.780"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12136"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.05.00034805"},{"key":"e_1_2_10_33_1","unstructured":"Team RC R: A Language and Environment for Statistical Computing https:\/\/www.r\u2010project.org\/."},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12667"},{"key":"e_1_2_10_35_1","volume-title":"Exposure\u2010Response Analysis of Dupilumab on Fored Expiratory Volume in 1 Second (FEV1) in Uncontrolled Persistent Asthma","author":"Zhang L.","year":"2017"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13601-019-0282-7"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-013-9463-9"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-010-9180-2"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.803"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70057","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T03:59:40Z","timestamp":1755489580000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.70057"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,19]]},"references-count":38,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1002\/psp4.70057"],"URL":"https:\/\/doi.org\/10.1002\/psp4.70057","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,19]]},"assertion":[{"value":"2024-12-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}