{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T20:01:44Z","timestamp":1766088104266,"version":"3.40.5"},"reference-count":19,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T00:00:00Z","timestamp":1690156800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:p>Oral azacitidine (oral\u2010AZA) maintenance is approved for adults with acute myeloid leukemia (AML) in remission post\u2010intensive chemotherapy, not proceeding to hematopoietic stem cell transplantation. This study aimed to develop a population pharmacokinetic (PopPK) model to characterize oral\u2010AZA concentration\u2013time profiles in patients with AML, myelodysplastic syndrome, or chronic myelomonocytic leukemia. PopPK\u2010estimated exposure parameters were used to evaluate exposure\u2013response relationships in the phase III QUAZAR AML\u2010001 study. The PopPK dataset comprised 286 patients with 1,933 evaluable oral\u2010AZA concentration records. The final PopPK model was a one\u2010compartment model with first\u2010order absorption incorporating an absorption lag time and first\u2010order elimination. Regression analyses identified two oral\u2010AZA exposure parameters (area under the plasma concentration\u2013time curve at steady state (AUC<jats:sub>ss<\/jats:sub>); maximum plasma concentration (<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>)) as statistically significant predictors for relapse\u2010free survival (hazard ratio (HR)\u2009=\u20090.521, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001; HR\u2009=\u20090.630, <jats:italic>P<\/jats:italic>\u2009=\u20090.013; respectively), and AUC<jats:sub>ss<\/jats:sub> as a significant predictor for overall survival (HR\u2009=\u20090.673, <jats:italic>P<\/jats:italic>\u2009=\u20090.042). The probability of grade \u2265\u20093 neutropenia was significantly increased with increases in AUC<jats:sub>ss<\/jats:sub> (odds ratio (OR)\u2009=\u20095.71, 95% confidence interval (CI)\u2009=\u20092.73\u201312.62, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001), cumulative AUC through cycles 1 to 6 (OR\u2009=\u20092.71, 95% CI\u2009=\u20091.76\u20134.44, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001), and <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> at steady\u2010state (OR\u2009=\u20092.38, 95% CI\u2009=\u20091.23\u20134.76, <jats:italic>P<\/jats:italic>\u2009=\u20090.012). A decreasing trend was identified between AUC<jats:sub>ss<\/jats:sub> and relapse\u2010related schedule extensions, vs. an increasing trend between AUC<jats:sub>ss<\/jats:sub> and event\u2010related dose reductions. As the majority (56.8%) of patients required no dose modifications, and the proportions requiring schedule extension (19.4%) or dose reduction (22.9%) were almost equal, oral\u2010AZA 300\u2009mg once daily for 14\u2009days is the optimal dosing schedule balancing survival benefit and safety risk.<\/jats:p>","DOI":"10.1002\/cpt.2982","type":"journal-article","created":{"date-parts":[[2023,7,9]],"date-time":"2023-07-09T03:15:36Z","timestamp":1688872536000},"page":"845-852","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Population Pharmacokinetics of Oral Azacitidine, and Exposure\u2013Response Analysis in Acute Myeloid Leukemia"],"prefix":"10.1111","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7677-5927","authenticated-orcid":false,"given":"Allison","family":"Gaudy","sequence":"first","affiliation":[{"name":"Bristol Myers Squibb  Summit New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7823-0004","authenticated-orcid":false,"given":"Eric","family":"Laille","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Summit New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rochelle","family":"Bailey","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Summit New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Zhou","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Summit New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barry","family":"Skikne","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Summit New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C.L.","family":"Beach","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb  Summit New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,7,24]]},"reference":[{"key":"e_1_2_12_1_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-08-0411"},{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-11-382226"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-016-0585-0"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.23607"},{"volume-title":"ONUREG [package insert]","year":"2021","key":"e_1_2_12_5_1"},{"volume-title":"ONUREG [summary of product characteristics]","year":"2021","key":"e_1_2_12_6_1"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2004444"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-021-01142-x"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clml.2021.09.021"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.34.4226"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.265"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0135520"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.25216"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-020-04037-9"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2004.22.90140.6051"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.HS9.0000844880.16190.70"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/phar.1371"},{"key":"e_1_2_12_18_1","first-page":"1453","article-title":"The disposition and pharmacokinetics in humans of 5\u2010azacytidine administered intravenously as a bolus or by continuous infusion1","volume":"36","author":"Israili Z.H.","year":"1976","journal-title":"Cancer Res."},{"key":"e_1_2_12_19_1","first-page":"405","article-title":"Absorption, distribution, and excretion of 5\u2010azacytidine (NSC\u2010102816) in man","volume":"56","author":"Troetel W.M.","year":"1972","journal-title":"Cancer Chemother. Rep."}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.2982","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,2]],"date-time":"2024-01-02T04:35:36Z","timestamp":1704170136000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.2982"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,24]]},"references-count":19,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,10]]}},"alternative-id":["10.1002\/cpt.2982"],"URL":"https:\/\/doi.org\/10.1002\/cpt.2982","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"type":"print","value":"0009-9236"},{"type":"electronic","value":"1532-6535"}],"subject":[],"published":{"date-parts":[[2023,7,24]]},"assertion":[{"value":"2023-02-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}