{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:14:46Z","timestamp":1790309686075,"version":"4.1.0"},"reference-count":25,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2019,3,12]],"date-time":"2019-03-12T00:00:00Z","timestamp":1552348800000},"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","award":["GSK 202007"],"award-info":[{"award-number":["GSK 202007"]}],"id":[{"id":"10.13039\/100004330","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004330","name":"GlaxoSmithKline","doi-asserted-by":"publisher","award":["NCT02647281"],"award-info":[{"award-number":["NCT02647281"]}],"id":[{"id":"10.13039\/100004330","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Pharm in Drug Dev"],"published-print":{"date-parts":[[2019,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>GSK3389404 is a liver\u2010targeted antisense oligonucleotide that inhibits synthesis of hepatitis B surface antigen and all other hepatitis B virus proteins. This first\u2010in\u2010human, randomized, double\u2010blind, phase 1 study assessed the safety and pharmacokinetics of GSK3389404 administered subcutaneously (SC) in healthy subjects. Four single ascending\u2010dose cohorts (10\u00a0mg, 30\u00a0mg, 60\u00a0mg, and 120 mg) and 3 multiple ascending\u2010dose cohorts (30\u00a0mg, 60\u00a0mg, and 120\u00a0mg once weekly for 4 weeks) each comprised 6 subjects randomized to GSK3389404 and 2 subjects randomized to placebo. There were no serious adverse events (AEs) or withdrawals due to AEs. The safety profile did not worsen with repeated dosing. The most frequent treatment\u2010related AEs were injection site reactions (19.0% [n\u00a0=\u00a08\/42], frequency unrelated to dose levels); all were mild (Grade 1) and resolved without dose modification or discontinuation. GSK3389404 administered subcutaneously was readily absorbed with a time to maximum plasma concentration (T<jats:sub>max<\/jats:sub>) of 1\u20134\u00a0hours and an elimination half\u2010life of 3\u20136\u00a0hours in plasma. Plasma area under the concentration\u2010time curve (AUC) and maximum observed concentration (C<jats:sub>max<\/jats:sub>) were dose\u2010proportional. Dose\u2010normalized plasma AUC from time 0 to infinity averaged 69.9\u00a0ng\u00b7h\/(mL\u00b7mg dose) across cohorts, and C<jats:sub>max<\/jats:sub> 9.5\u00a0ng\/(mL\u00b7mg dose). Pharmacokinetic profiles and parameters were comparable between single and multiple dosing. No accumulation was observed with once\u2010weekly dosing. The metabolite was undetectable in urine and plasma. In the pooled urine, GSK3389404 was estimated to account for &lt;0.1% of the total dose. In summary, GSK3389404 dosing has been tested up to 120\u00a0mg for 4\u00a0weeks with an acceptable safety and pharmacokinetic profile, supporting further clinical investigation in patients with chronic hepatitis B.<\/jats:p>","DOI":"10.1002\/cpdd.670","type":"journal-article","created":{"date-parts":[[2019,3,12]],"date-time":"2019-03-12T16:16:20Z","timestamp":1552407380000},"page":"790-801","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["A Randomized, Double\u2010Blind, Placebo\u2010Controlled, First\u2010Time\u2010in\u2010Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of GSK3389404 in Healthy Subjects"],"prefix":"10.1002","volume":"8","author":[{"given":"Kelong","family":"Han","sequence":"first","affiliation":[{"name":"GlaxoSmithKline  Collegeville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Cremer","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Elston","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline  Stevenage Hertfordshire UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"Oliver","sequence":"additional","affiliation":[{"name":"IQVIA  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Baptiste\u2010Brown","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline  Collegeville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuguang","family":"Chen","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline  Collegeville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Gardiner","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline  Collegeville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"Davies","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline  Stockley Park Uxbridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Saunders","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline  Collegeville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Hamatake","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Losos","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Leivers","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Hood","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline  Stevenage Hertfordshire UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frans","family":"van der Berg","sequence":"additional","affiliation":[{"name":"Hammersmith Medicines Research  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Paff","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Ritter","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dickens","family":"Theodore","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,3,12]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2012.02.010"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2011.12.116"},{"key":"e_1_2_9_4_1","unstructured":"World Health Organization.Global Hepatitis Report.2017.http:\/\/apps.who.int\/iris\/bitstream\/handle\/10665\/255016\/9789241565455-eng.pdf?sequence=1. 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