{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:52:12Z","timestamp":1792173132901,"version":"4.4.0"},"reference-count":43,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"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":["Clinical Translational Sci"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Sj\u00f6gren's disease (SD) is an autoimmune condition characterized by chronic inflammation and impaired secretory function of the salivary glands (SG). The proresolving lipid mediator AT\u2010RvD1 restores SG function in SD\u2010like mice; however, its tissue pharmacokinetics, exposure\u2010response relationships, and human dose predictions remain poorly understood. Therefore, this exploratory study characterizes AT\u2010RvD1 tissue pharmacokinetics, develops an SG\u2010focused physiologically based pharmacokinetic (PBPK) model, explores the relationship between SG exposure and secretory response, and predicts human exposures relevant to clinical development. Following intravenous administration of AT\u2010RvD1 to SD\u2010like mice, concentrations were quantified in serum, submandibular gland (SMG), heart, lung, liver, and kidney. These data were used to evaluate a PBPK model incorporating the SG as the target site of action. PBPK\u2010predicted cumulative SMG exposure was subsequently compared with the saliva flow rate obtained after chronic AT\u2010RvD1 treatment. The mouse model was then used to predict systemic and SG exposure in a virtual human population across an exploratory dose range. The PBPK model described systemic and tissue pharmacokinetics, with average fold error and absolute average fold error values within predefined acceptance criteria. Human PBPK simulations predicted dose\u2010dependent increases in SG exposure and identified 1.5\u2009mg\/kg as a candidate dose at which predicted concentrations exceeded the preclinical pharmacological reference concentration in more than 90% of simulated subjects. Collectively, these analyses provide an experimentally informed PBPK framework for exploring AT\u2010RvD1 tissue exposure, exposure\u2013response relationships, and candidate doses for future clinical evaluation in SD.<\/jats:p>","DOI":"10.1111\/cts.70741","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T12:47:30Z","timestamp":1791463650000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Translational\n                    <scp>PBPK<\/scp>\n                    Modeling and Exposure\u2010Response Analysis of\n                    <scp>AT<\/scp>\n                    \u2010\n                    <scp>RvD1<\/scp>\n                    for Treating Sj\u00f6gren's Disease"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3819-9054","authenticated-orcid":false,"given":"Venkata K.","family":"Yellepeddi","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Pediatrics, Spencer Fox Eccles School of Medicine University of Utah  Salt Lake City Utah USA"},{"name":"Department of Molecular Pharmaceutics, College of Pharmacy University of Utah  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8934-4886","authenticated-orcid":false,"given":"Kihoon","family":"Nam","sequence":"additional","affiliation":[{"name":"Christopher S. Bond Life Sciences Center  Columbia Missouri USA"},{"name":"Department of Otolaryngology\u2010Head and Neck Surgery, School of Medicine University of Missouri  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0232-3876","authenticated-orcid":false,"given":"Frank M.","family":"Maslow","sequence":"additional","affiliation":[{"name":"Christopher S. Bond Life Sciences Center  Columbia Missouri USA"},{"name":"Department of Otolaryngology\u2010Head and Neck Surgery, School of Medicine University of Missouri  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0628-8645","authenticated-orcid":false,"given":"Olga J.","family":"Baker","sequence":"additional","affiliation":[{"name":"Christopher S. Bond Life Sciences Center  Columbia Missouri USA"},{"name":"Department of Otolaryngology\u2010Head and Neck Surgery, School of Medicine University of Missouri  Columbia Missouri USA"},{"name":"Department of Biochemistry, School of Medicine University of Missouri  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,8]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10238-021-00728-6"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-2776(08)60641-0"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/1477-7525-7-46"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm15051945"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2024-004310"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI13375"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pathmechdis.3.121806.151409"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1101665"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2015.129"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201601222R"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M609212200"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2025.103896"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-025-02320-6"},{"key":"e_1_2_12_15_1","first-page":"100046","article-title":"Current Basic and Preclinical Research for Treatment of Radiation Therapy\u2010Induced Hyposalivation","volume":"4","author":"Baker O. J.","year":"2025","journal-title":"Journal of Advanced Dental and Oral Health Foundational Science"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00284.2013"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00207.2011"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00259.2011"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep24244"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2018.04.003"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.23937\/2469-5726\/1510027"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep45525"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12930"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2013.05.012"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.192.8.1197"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kez072"},{"key":"e_1_2_12_27_1","first-page":"1","article-title":"A Combination Treatment of Low\u2010Dose Dexamethasone and Aspirin\u2010Triggered Resolvin D1 Reduces Sjogren Syndrome\u2010Like Features in a Mouse Model","volume":"2","author":"Dos Santos H. T.","year":"2023","journal-title":"JADA Foundational Science"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.37"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-018-0677-y"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010510-100540"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12134"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/cre2.260"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1538\/expanim1978.29.1_1"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1094278"},{"key":"e_1_2_12_35_1","unstructured":"Open Systems Pharmacology \u201cPK\u2010Sim and MoBi [Software] \u201dVersion 12.2 https:\/\/open\u2010systems\u2010pharmacology.org\/."},{"key":"e_1_2_12_36_1","volume-title":"Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers","author":"U.S. Food and Drug Administration","year":"2025"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01784-16"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.25.1084"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01292-17"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-54410-9"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm15031189"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-210571"},{"key":"e_1_2_12_43_1","article-title":"A Method for the Measurement of Salivary Gland Function in Mice","volume":"131","author":"Bagavant H.","year":"2018","journal-title":"Journal of Visualized Experiments"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1111\/odi.12840"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70741","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.70741","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70741","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:18:06Z","timestamp":1792171086000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.70741"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10]]},"references-count":43,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1111\/cts.70741"],"URL":"https:\/\/doi.org\/10.1111\/cts.70741","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10]]},"assertion":[{"value":"2026-06-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70741"}}