{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T23:55:55Z","timestamp":1790207755334,"version":"4.1.0"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2024,1,27]],"date-time":"2024-01-27T00:00:00Z","timestamp":1706313600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,1,27]],"date-time":"2024-01-27T00:00:00Z","timestamp":1706313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100016471","name":"Agios Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016471","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Chemother Pharmacol"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>Report pharmacokinetic (PK)\/pharmacodynamic (PD) findings from the phase III ClarIDHy study and any association between PK\/PD parameters and treatment outcomes in this population.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Patients with mutant isocitrate dehydrogenase 1 (m<jats:italic>IDH1<\/jats:italic>) advanced cholangiocarcinoma were randomized at a 2:1 ratio to receive ivosidenib or matched placebo. Crossover from placebo to ivosidenib was permitted at radiographic disease progression. Blood samples for PK\/PD analyses, a secondary endpoint, were collected pre-dose and up to 4 h post-dose on day (D) 1 of cycles (C) 1\u2009\u2212\u20092, pre-dose and 2 h post-dose on D15 of C1\u2009\u2212\u20092, and pre-dose on D1 from C3 onwards. Plasma ivosidenib and D-2-hydroxyglutarate (2-HG) were measured using liquid chromatography-tandem mass spectrometry. All clinical responses were centrally reviewed previously.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>PK\/PD analysis was available for samples from 156 ivosidenib-treated patients. Ivosidenib was absorbed rapidly following single and multiple oral doses (time of maximum observed plasma concentration [<jats:italic>T<\/jats:italic><jats:sub>max<\/jats:sub>] of 2.63 and 2.07 h, respectively). Ivosidenib exposure was higher at C2D1 than after a single dose, with low accumulation. In ivosidenib-treated patients, mean plasma 2-HG concentration was reduced from 1108\u00a0ng\/mL at baseline to 97.7\u00a0ng\/mL at C2D1, close to levels previously observed in healthy individuals. An average 2-HG inhibition of 75.0% was observed at steady state. No plasma 2-HG decreases were seen with placebo. Plasma 2-HG reductions were observed in ivosidenib-treated patients irrespective of best overall response (progressive disease, or partial response and stable disease).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Once-daily ivosidenib 500\u00a0mg has a favorable PK\/PD profile, attesting the 2-HG reduction mechanism of action and, thus, positive outcomes in treated patients with advanced m<jats:italic>IDH1<\/jats:italic> cholangiocarcinoma.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Clinical trial registration<\/jats:title>\n                <jats:p>NCT02989857 Registered February 20, 2017.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00280-023-04633-5","type":"journal-article","created":{"date-parts":[[2024,1,27]],"date-time":"2024-01-27T02:04:15Z","timestamp":1706321055000},"page":"471-479","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Pharmacokinetics\/pharmacodynamics of ivosidenib in advanced IDH1-mutant cholangiocarcinoma: findings from the phase III ClarIDHy study"],"prefix":"10.1007","volume":"93","clinical-trial-number":[{"clinical-trial-number":"nct02989857","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Bin","family":"Fan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghassan K.","family":"Abou-Alfa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew X.","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuchi S.","family":"Pandya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxia","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camelia","family":"Gliser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaowei","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9147-7917","authenticated-orcid":false,"given":"Mohammad","family":"Hossain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,27]]},"reference":[{"key":"4633_CR1","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1634\/theoncologist.2011-0386","volume":"17","author":"DR Borger","year":"2012","unstructured":"Borger DR, Tanabe KK, Fan KC, Lopez HU, Fantin VR, Straley KS et al (2012) Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. 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GKA has received research grant\/funding from Arcus, AstraZeneca, BioNtech, Bristol Myers Squibb, Celgene, Flatiron, Genentech\/Roche, Genoscience, Incyte, Polaris, Puma, QED, Silenseed, and Yiviva; and serves as a consultant for Adicet, Alnylam, AstraZeneca, Autem, Beigene, Berry Genomics, Boehringer Ingelheim, Celgene, Cend, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech\/Roche, Genoscience, Helio, Helsinn, Incyte, Ipsen, Merck, Nerviano, Newbridge, Novartis, QED, Rafael, Redhill, Servier, Silenseed, Sobi, Vector, and Yiviva. AXZ is an employee of I-Mab Biopharma; has participated in advisory boards for AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, Exelixis, Merck, Novartis, and Roche\/Genentech; and has received research grant\/funding from Bayer, Bristol Myers Squibb, Eli Lilly, Merck, and Novartis. SSP, CG, and MH were employees and stockholders of Agios Pharmaceuticals, Inc., at the time of the study, and are now employees of Servier Pharmaceuticals LLC. HJ was an employee and stockholder of Agios Pharmaceuticals, Inc., at the time of the study, and is now employee of Takeda Pharmaceutical Company Ltd. ZH is an employee of Servier Pharmaceuticals LLC.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This study was conducted according to the International Council for Harmonisation of Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Approval from the institutional review board and independent ethics committee was obtained by all study investigators. Informed consent was obtained from all patients included in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}