{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:24:00Z","timestamp":1792009440091,"version":"4.4.0"},"reference-count":35,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2018,7,12]],"date-time":"2018-07-12T00:00:00Z","timestamp":1531353600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004330","name":"GlaxoSmithKline","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004330","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2018,10]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>The oncostatin M (OSM) pathway drives fibrosis, inflammation and vasculopathy, and is a potential therapeutic target for inflammatory and fibrotic diseases. The aim of this first\u2010time\u2010in\u2010human experimental medicine study was to assess the safety, tolerability, pharmacokinetics and target engagement of single subcutaneous doses of GSK2330811, an anti\u2010OSM monoclonal antibody, in healthy subjects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This was a phase I, randomized, double\u2010blind, placebo\u2010controlled, single\u2010dose escalation, first\u2010time\u2010in\u2010human study of subcutaneously administered GSK2330811 in healthy adults (NCT02386436). Safety and tolerability, GSK2330811 pharmacokinetic profile, OSM levels in blood and skin, and the potential for antidrug antibody formation were assessed. The <jats:italic>in vivo<\/jats:italic> affinity of GSK2330811 for OSM and target engagement in serum and skin blister fluid (obtained via a skin suction blister model) were estimated using target\u2010mediated drug disposition (TMDD) models in combination with compartmental and physiology\u2010based pharmacokinetic (PBPK) models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Thirty subjects were randomized to receive GSK2330811 and 10 to placebo in this completed study. GSK2330811 demonstrated a favourable safety profile in healthy subjects; no adverse events were serious or led to withdrawal. There were no clinically relevant trends in change from baseline in laboratory values, with the exception of a reversible dose\u2010dependent reduction in platelet count. GSK2330811 exhibited linear pharmacokinetics over the dose range 0.1\u20136\u00a0mg kg<jats:sup>\u20131<\/jats:sup>. The estimated <jats:italic>in vivo<\/jats:italic> affinity (nM) of GSK2330811 for OSM was 0.568 [95% confidence interval (CI) 0.455, 0.710] in the compartmental with TMDD model and 0.629 (95% CI 0.494, 0.802) using the minimal PBPK with TMDD model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Single subcutaneous doses of GSK2330811 were well tolerated in healthy subjects. GSK2330811 demonstrated sufficient affinity to achieve target engagement in systemic circulation and target skin tissue, supporting the progression of GSK2330811 clinical development.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.13669","type":"journal-article","created":{"date-parts":[[2018,6,14]],"date-time":"2018-06-14T05:50:54Z","timestamp":1528955454000},"page":"2280-2291","source":"Crossref","is-referenced-by-count":50,"title":["<i>In vivo<\/i> affinity and target engagement in skin and blood in a first\u2010time\u2010in\u2010human study of an anti\u2010oncostatin M monoclonal antibody"],"prefix":"10.1111","volume":"84","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3530-750X","authenticated-orcid":false,"given":"Juliet","family":"Reid","sequence":"first","affiliation":[{"name":"ImmunoInflammation GlaxoSmithKline  Stevenage UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Zamuner","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology GlaxoSmithKline  Stevenage UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Edwards","sequence":"additional","affiliation":[{"name":"Statistics GlaxoSmithKline  Stevenage UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally\u2010Anne","family":"Rumley","sequence":"additional","affiliation":[{"name":"Clinical Platforms and Sciences GlaxoSmithKline  Stevenage UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Nevin","sequence":"additional","affiliation":[{"name":"ImmunoInflammation GlaxoSmithKline  Stevenage UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Feeney","sequence":"additional","affiliation":[{"name":"Biopharm Research GlaxoSmithKline  Stevenage UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Zecchin","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology GlaxoSmithKline  Stevenage UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Disala","family":"Fernando","sequence":"additional","affiliation":[{"name":"Clinical Unit Cambridge GlaxoSmithKline  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Wisniacki","sequence":"additional","affiliation":[{"name":"ImmunoInflammation GlaxoSmithKline  Stevenage UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,7,12]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.51.32635"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1542794"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2015.07.006"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.10.7243"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/512103"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-02-0367"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4307"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29421"},{"issue":"10","key":"e_1_2_9_10_1","first-page":"1","article-title":"Oncostatin M as a potential molecular target in systemic sclerosis","volume":"67","author":"Feeney M","year":"2015","journal-title":"Arthritis Rheumatol"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2015.2"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar4312"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115775"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-015-0575-8"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/cei.12107"},{"key":"e_1_2_9_16_1","unstructured":"Committee for Medicinal Products for Human Use.Guideline on strategies to identify and mitigate risks for first\u2010in\u2010human clinical trials with investigational medicinal products.2007. 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