{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T02:52:52Z","timestamp":1794019972431,"version":"4.8.0"},"reference-count":26,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,12,3]],"date-time":"2023-12-03T00:00:00Z","timestamp":1701561600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:p>Increase in serum bile acids (BAs) in patients with primary biliary cholangitis (PBC) may play a causal role in cholestatic pruritus (itch). Linerixibat is a selective small molecule inhibitor of the ileal bile acid transporter, which blocks re\u2010absorption of BAs in the gastrointestinal tract thereby lowering BAs in the systemic circulation and reducing itch. One consequence is excess BAs in the colon, leading to diarrhea and abdominal pain. GLIMMER (NCT02966834) was a placebo\u2010controlled phase IIb dose\u2010ranging trial of linerixibat once (q.d.) or twice daily (b.i.d.) in adults with moderate to severe pruritus and PBC. To determine the optimal dose for maximum itch reduction while minimizing diarrhea, a kinetic\u2010pharmacodynamic (k\u2010PD) model was developed using data from GLIMMER. The PD end point modeled was worst daily itch, derived from itch score reported by patients b.i.d. A proportional odds model was developed <jats:italic>post hoc<\/jats:italic> to indicate the probability of diarrhea occurrence, a patient\u2010reported outcome (GI\u20105) recorded weekly. The final k\u2010PD model successfully described the effects of linerixibat and placebo on itch. Model simulations were consistent with the observed dose\u2010dependent increase in the average number of itch responders (patients with a\u2009\u2265\u20092\u2010point improvement in itch). This was paralleled by a dose\u2010dependent increase in the probability of higher diarrhea frequency scores. The b.i.d. dosing regimens led to a modest increase in the number of itch responders as compared with q.d. dosing. This quantitative framework highlights the trade\u2010off between benefit and tolerability and supported the selection of 40\u2009mg b.i.d. in the phase III GLISTEN trial (NCT04950127).<\/jats:p>","DOI":"10.1002\/cpt.3103","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T05:36:30Z","timestamp":1699853790000},"page":"288-298","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Population Dose\u2013Response\u2010Time Analysis of Itch Reduction and Patient\u2010Reported Tolerability Supports Phase III Dose Selection for Linerixibat"],"prefix":"10.1002","volume":"115","author":[{"given":"Fernando","family":"Carre\u00f1o","sequence":"first","affiliation":[{"name":"UNC Eshelman School of Pharmacy The University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"},{"name":"GSK  Collegeville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Karatza","sequence":"additional","affiliation":[{"name":"UNC Eshelman School of Pharmacy The University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"},{"name":"GSK  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashmi","family":"Mehta","sequence":"additional","affiliation":[{"name":"GSK  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Collins","sequence":"additional","affiliation":[{"name":"GSK  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daren","family":"Austin","sequence":"additional","affiliation":[{"name":"GSK  Brentford, Middlesex UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4179-4842","authenticated-orcid":false,"given":"Brandon","family":"Swift","sequence":"additional","affiliation":[{"name":"GSK  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,12,3]]},"reference":[{"key":"e_1_2_11_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12196"},{"key":"e_1_2_11_2_1","first-page":"654","article-title":"The importance of dose optimization prior to initiation of a registration trial","volume":"14","author":"Rahman N.A.","year":"2016","journal-title":"Clin. 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