{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T13:20:04Z","timestamp":1787664004937,"version":"build-2736575974"},"reference-count":18,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T00:00:00Z","timestamp":1787443200000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100005564","name":"Gilead Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005564","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Tilpisertib fosmecarbil (TIP; GS\u20105290) is an intestinally cleaved prodrug of GS\u20104875, a potent tumor progression locus 2 (TPL2) inhibitor being investigated for ulcerative colitis (UC). The pharmacokinetics, pharmacodynamics, and safety of single or multiple (over 10 days) oral doses of TIP (N = 73; 75\u20101500 mg) or GS\u20104875 (N = 82; 15\u2010450 mg) were assessed in two randomized, placebo\u2010controlled studies in healthy participants. A third study (N = 32) assessed the renal effects of GS\u20104875 (300 mg daily) due to observed serum creatinine increases. TIP was generally undetectable in plasma after administration, indicating rapid conversion to GS\u20104875. GS\u20104875 had a half\u2010life of 19\u201029 h after TIP administration and exposure was greater than with mg\u2010equivalent doses of GS\u20104875 (population mean [90% CI] AUC\n                    <jats:sub>tau<\/jats:sub>\n                    slope: 0.72 [0.59\u20100.85] versus 0.57 [0.47\u20100.67]). Inhibition of lipopolysaccharide\u2010stimulated phosphorylated extracellular signal\u2010regulated kinase (a TPL2 pathway pharmacodynamic biomarker) 24 h post last dose was greater with TIP versus GS\u20104875 dosing (&gt;90% [TIP 300\u2010900 mg] versus 75\u201080% [GS\u20104875 450 mg]). Investigator\u2010assessed, study drug\u2010related adverse events (AEs) occurred in 9.3% (5\/54) of TIP recipients and 5.3% (1\/19) of placebo recipients (all grade 1 severity). No serious AEs or deaths occurred. GS\u20104875 and TIP reduced creatinine\u2010based estimated glomerular filtration rate (GFR; day 10 baseline\u2010adjusted geometric least\u2010squares means ratio [90% CI] for GS\u20104875\/placebo: 83.3% [79.2\u201087.5%]); this was attributed to renal transporter inhibition rather than GFR impairment as cystatin C\u2010 and iohexol\u2010based GFR were unchanged. These data support further development of TIP in an ongoing phase 2 trial in UC (NCT06029972).\n                  <\/jats:p>","DOI":"10.1002\/jcph.70269","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T05:57:11Z","timestamp":1787551031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["First\u2010In\u2010Human Evaluation of the Pharmacokinetics, Pharmacodynamics, and Safety of Tilpisertib Fosmecarbil (GS\u20105290), an Oral Prodrug of a Tumor Progression Locus 2 Inhibitor in Healthy Participants"],"prefix":"10.1002","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3351-6881","authenticated-orcid":false,"given":"Priyanka A.","family":"Madia","sequence":"first","affiliation":[{"name":"Gilead Sciences  Foster City California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily R.","family":"Wendt","sequence":"additional","affiliation":[{"name":"Gilead Sciences  Foster City California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann Ran\u2010Ran","family":"Qin","sequence":"additional","affiliation":[{"name":"Gilead Sciences  Foster City California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7253-2216","authenticated-orcid":false,"given":"Xin","family":"Qi","sequence":"additional","affiliation":[{"name":"Gilead Sciences  Foster City California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Liang","sequence":"additional","affiliation":[{"name":"Gilead Sciences  Foster City California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shital","family":"Kalariya","sequence":"additional","affiliation":[{"name":"Gilead Sciences  Foster City California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Hong","sequence":"additional","affiliation":[{"name":"Gilead Sciences  Foster City California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eda","family":"Canales","sequence":"additional","affiliation":[{"name":"Gilead Sciences  Foster City California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James G.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Gilead Sciences  Foster City California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Udayasankar","family":"Arulmani","sequence":"additional","affiliation":[{"name":"Gilead Sciences  Foster City California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarundeep","family":"Kakkar","sequence":"additional","affiliation":[{"name":"Gilead Sciences  Foster City California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)32126-2"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10209"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-0205-x"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2016.208"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/ecco-jcc\/jjx009"},{"issue":"1","key":"e_1_2_10_7_1","first-page":"64","article-title":"Refractory ulcerative colitis treatment","volume":"3","author":"Macdermott RP","year":"2007","journal-title":"Gastroenterol Hepatol (N Y)"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2010.173"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11582"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2014-308922"},{"key":"e_1_2_10_11_1","unstructured":"U.S. Department of Health and Human Services Food and Drug Administration.Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers.2005. Accessed August 14 2026.https:\/\/www.fda.gov\/media\/72309\/download."},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1114248"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-008-9014-y"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/mp4001348"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v19.i38.6398"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.me.39.020188.002341"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2009020171"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2021.04.016"},{"key":"e_1_2_10_19_1","unstructured":"GE Healthcare Inc.OMNIPAQUE (iohexol) injection: GE Healthcare.2017. 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