{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T22:31:12Z","timestamp":1781735472678,"version":"3.54.5"},"reference-count":27,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T00:00:00Z","timestamp":1710288000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>As the first\u2010in\u2010class, selective, and potent inhibitor of the isocitrate dehydrogenase\u20102 (IDH2) mutant protein, enasidenib was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation. Known for its interactions with various cytochrome P450 (CYP)\u00a0enzymes and transporters in vitro, a clinical pharmacokinetics (PK) trial was initiated to assess the impact of multiple doses of enasidenib on the single\u2010dose PK of sensitive probe substrates of several cytochrome P450 enzymes and transporters. In this study, a population pharmacokinetic analysis approach was employed to address challenges posed by high, nonzero baseline caffeine concentrations. Moreover, we integrated full Bayesian inference into this approach innovatively for a more detailed understanding of parameter uncertainty and greater modeling flexibility, alongside Student's t\u2010distribution for robust error modeling in handling the abnormal outlier caffeine concentration data observed in this trial. Our analyses demonstrated that multiple doses of enasidenib altered caffeine clearance to a clinically meaningful extent, as evidenced by an approximate 8\u2010fold decrease. This finding led to a specific recommendation in the package insert to avoid the concurrent use of certain CYP1A2 substrates with enasidenib, unless directed otherwise in the prescribing information. Furthermore, this research underlines the technical benefits of integrating full Bayesian inference and incorporating Student's t\u2010distribution for residual error modeling in the PK field.<\/jats:p>","DOI":"10.1002\/jcph.2426","type":"journal-article","created":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T16:03:26Z","timestamp":1710345806000},"page":"866-877","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Integrating Full Bayesian Inference and Student's t\u2010Distribution Method for Enhanced Outlier Handling in Caffeine Population Pharmacokinetics: Assessing Drug\u2013Drug Interactions with Enasidenib in Relapsed or Refractory AML and MDS Patients"],"prefix":"10.1002","volume":"64","author":[{"given":"Yiming","family":"Cheng","sequence":"first","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Bristol Myers Squibb  Summit NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengnan","family":"Du","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Bristol Myers Squibb  Lawrenceville NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxiang","family":"Hu","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Bristol Myers Squibb  Summit NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomin","family":"Wang","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Bristol Myers Squibb  Summit NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon","family":"Carayannopoulos","sequence":"additional","affiliation":[{"name":"Early Clinical Development Bristol Myers Squibb  Summit NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Bristol Myers Squibb  Summit NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,3,13]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-0536"},{"issue":"4","key":"e_1_2_11_3_1","first-page":"247","article-title":"Enasidenib for patients with relapsed acute myeloid leukemia and the IDH2 mutation","volume":"16","author":"DiNardo C","year":"2018","journal-title":"Clin Adv Hematol Oncol"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1080\/17512433.2018.1477585"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.2174\/1568026618666180518091144"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-04-779405"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2010.11.015"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1231677"},{"key":"e_1_2_11_9_1","unstructured":"IDHIFA\u00ae (enasidenib) [package insert]. Summit NJ USA: Celgene Cooporation;2022.https:\/\/packageinserts.bms.com\/pi\/pi_idhifa.pdf. Accessed December 1 2023"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2023010563"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1979"},{"key":"e_1_2_11_12_1","first-page":"39","article-title":"Modeling and simulation of the endogenous CYP3A induction marker 4beta\u2010hydroxycholesterol during enasidenib treatment","volume":"11","author":"Li Y","year":"2019","journal-title":"Clin Pharmacol"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.436"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/00498254.2018.1425511"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.12586"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.3109\/00498254.2012.739719"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2014.06.022"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.406"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-015-0283-1"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2010.158"},{"key":"e_1_2_11_21_1","unstructured":"BauerRJ.Technical Guide on Various Methods in NONMEM 7.2020.https:\/\/nonmem.iconplc.com\/nonmem750\/guides\/NONMEM7_Technical_Guide.pdf. Accessed November 1 2023"},{"key":"e_1_2_11_22_1","unstructured":"BauerRJ.NONMEM USERS GUIDE INTRODUCTION TO NONMEM 7.5.0.2020.https:\/\/nonmem.iconplc.com\/nonmem750\/guides. Accessed November 1 2023."},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-7843.2005.pto960111.x"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2019.04.005"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13318-021-00707-y"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1020206907668"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12926"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-015-9460-y"}],"container-title":["The Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.2426","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,25]],"date-time":"2024-06-25T12:25:29Z","timestamp":1719318329000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/jcph.2426"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,13]]},"references-count":27,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2024,7]]}},"alternative-id":["10.1002\/jcph.2426"],"URL":"https:\/\/doi.org\/10.1002\/jcph.2426","archive":["Portico"],"relation":{},"ISSN":["0091-2700","1552-4604"],"issn-type":[{"value":"0091-2700","type":"print"},{"value":"1552-4604","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,13]]},"assertion":[{"value":"2024-01-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-03-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}