{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T23:44:18Z","timestamp":1776901458486,"version":"3.51.2"},"reference-count":36,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"abstract":"<jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>Intradermal application of lipopolysaccharide (LPS), a Toll\u2010like receptor 4 agonist, induces a local inflammatory response and is used as a human challenge model to evaluate the pharmacodynamics of investigational medicinal products. While currently applied in a single, parallel\u2010group setting, alternative within\u2010subject designs involving repeated LPS challenges at different skin sites and spaced across multiple timepoints would enable within\u2010subject comparisons, potentially reducing inter\u2010individual variability in pharmacodynamic assessments. We aimed to determine whether intradermal LPS challenges at different sites on the back, with 14\u2010day intervals, would be an optimal design for clinical pharmacology studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Eight healthy volunteers received seven 5\u2010ng intradermal LPS injections: six on the back on Days 1, 15 and 29 (two per day) and one on the volar forearm on Day 1. Local inflammation was assessed via non\u2010invasive imaging (skin perfusion and erythema) and suction blister fluid (cytokines and leukocytes) at 10\u2010 and 24 h post\u2010injection. Systemic responses were evaluated through blood cytokine and leukocyte levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Repeated intradermal LPS challenges were well tolerated. Skin perfusion, erythema and local cytokine and chemokine levels were similar across challenges. However, on subsequent challenge days there were shifts in vascular responses and counts of classical monocyte, and other leukocytes in blister fluid were reduced at 10\u2009h on Day 15 compared to Day 1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The results indicate that following Day 1 intradermal LPS challenges, a subtle immune adaptation may occur, potentially limiting the model's reliability for cellular endpoint\u2010focused within\u2010subject pharmacological investigations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bcp.70572","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T23:09:45Z","timestamp":1776899385000},"source":"Crossref","is-referenced-by-count":0,"title":["Repeated intradermal lipopolysaccharide challenge responses in healthy volunteers: Implications for clinical pharmacology studies"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8258-2919","authenticated-orcid":false,"given":"Alexandra A. J.","family":"Sill\u00e9","sequence":"first","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"},{"name":"Leiden University Medical Centre  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7356-6847","authenticated-orcid":false,"given":"Juliette A.","family":"van den Noort","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"},{"name":"Leiden University Medical Centre  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iva","family":"Lelios","sequence":"additional","affiliation":[{"name":"Pharma Research and Early Development F. Hoffmann\u2010La Roche Ltd  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana R.","family":"Pereira","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marzia A.","family":"Scelsi","sequence":"additional","affiliation":[{"name":"Product Development Data Sciences Roche Products Ltd  Welwyn Garden City UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erica S.","family":"Klaassen","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philipp","family":"Schoenenberger","sequence":"additional","affiliation":[{"name":"Pharma Research and Early Development F. Hoffmann\u2010La Roche Ltd  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomi B.","family":"Klarenbeek","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"},{"name":"Leiden University Medical Centre  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierre\u2010Eric","family":"Juif","sequence":"additional","affiliation":[{"name":"Pharma Research and Early Development F. Hoffmann\u2010La Roche Ltd  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pascal","family":"Espie","sequence":"additional","affiliation":[{"name":"Pharma Research and Early Development F. Hoffmann\u2010La Roche Ltd  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manon A. 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