{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T20:06:53Z","timestamp":1789416413279,"version":"build-2803163510"},"reference-count":19,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Levothyroxine sodium has been the cornerstone of hypothyroidism management worldwide, with daily oral administration (PO) recognized as standard of care. Oral administration of levothyroxine, however, poses challenges due to variability in pharmacokinetics (PK), influenced by factors such as gastrointestinal absorption, food\/drug interactions, and patient adherence. XP\u20108121 (levothyroxine for subcutaneous administration) is a ready\u2010to\u2010use, subcutaneous (SC) injection formulation of levothyroxine in Phase 3 development. This Phase 1, single\u2010center, 2\u2010part study aimed to characterize the PK and dose proportionality of XP\u20108121 SC compared to 600\u2009\u03bcg oral Ievothyroxine in healthy adults. Additionally, the study evaluated the safety and tolerability of XP\u20108121 and incorporated population pharmacokinetic (PPK) modeling to support future development. Part 1 was a randomized, open\u2010label, crossover, fixed\u2010sequence study (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200930). Dose linearity was evaluated by escalating XP\u20108121 SC doses up to 1200\u2009\u03bcg. Part 2 was an open\u2010label, single\u2010period study (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200930) evaluating PK characteristics of a single dose of XP\u20108121 SC (1500\u2009\u03bcg), potential clinical exposure range, and dose proportionality. After oral levothyroxine administration, baseline\u2010adjusted levothyroxine concentration increased rapidly in plasma (\n                    <jats:italic>T<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    median: 3.1\u2009h); absorption for all XP\u20108121 SC doses was slower compared to 600\u2009\u03bcg oral levothyroxine, and levels remained elevated for 4\u20135\u2009days before decreasing. Dose proportionality was confirmed, and safety results were similar between all groups. PPK analysis results suggested that weekly doses of XP\u20108121 SC at four times the daily oral levothyroxine dose provide similar exposure at steady state (AUC\n                    <jats:sub>ss<\/jats:sub>\n                    ). Overall, these data for XP\u20108121 provide adequate predictive performance to inform future phase 2 studies.\n                  <\/jats:p>","DOI":"10.1111\/cts.70244","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T08:38:18Z","timestamp":1746779898000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Phase 1 Study Evaluating the Pharmacokinetics, Dose Proportionality, Bioavailability, and Tolerability of Subcutaneous Levothyroxine Sodium (\n                    <scp>XP<\/scp>\n                    \u20108121)"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0522-0699","authenticated-orcid":false,"given":"Richard","family":"Fitch","sequence":"first","affiliation":[{"name":"Xeris Pharmaceuticals, Inc.  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8908-0136","authenticated-orcid":false,"given":"Diane R.","family":"Mould","sequence":"additional","affiliation":[{"name":"Projections Research, Inc.  Phoenixville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2718-3306","authenticated-orcid":false,"given":"Valentina","family":"Conoscenti","sequence":"additional","affiliation":[{"name":"Xeris Pharmaceuticals, Inc.  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robbie","family":"Huang","sequence":"additional","affiliation":[{"name":"Xeris Pharmaceuticals, Inc.  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4195-7481","authenticated-orcid":false,"given":"Dawn","family":"Harper","sequence":"additional","affiliation":[{"name":"Xeris Pharmaceuticals, Inc.  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