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This study aimed to evaluate (1) the relationship between exposure to osimertinib, especially its active metabolites (AZ5104 and AZ7550), and AEs, and (2) the relationship between germline polymorphisms and AEs. <jats:bold>Methods:<\/jats:bold> We conducted a prospective, longitudinal observational study of 53 patients with advanced non-small cell lung cancer receiving osimertinib therapy from February 2019 to April 2022. A population pharmacokinetic model was developed to estimate the area under the serum concentration\u2013time curve from 0 to 24\u00a0h (AUC<jats:sub>0\u201324<\/jats:sub>) of osimertinib and its metabolites. Germline polymorphisms were analyzed using TaqMan\u00ae SNP genotyping and CycleavePCR\u00ae assays. <jats:bold>Results:<\/jats:bold> There was a significant association between the AUC<jats:sub>0\u201324<\/jats:sub> of AZ7550 and grade\u2009\u2265\u20092 paronychia (<jats:italic>p<\/jats:italic>\u2009=\u20090.043) or anorexia (<jats:italic>p<\/jats:italic>\u2009=\u20090.011) and between that of osimertinib or AZ5104 and grade\u2009\u2265\u20092 diarrhea (<jats:italic>p<\/jats:italic>\u2009=\u20090.026 and <jats:italic>p<\/jats:italic>\u2009=\u20090.049, respectively). Furthermore, the AUC<jats:sub>0\u201324<\/jats:sub> of AZ5104 was significantly associated with any grade\u2009\u2265\u20092 AEs (<jats:italic>p<\/jats:italic>\u2009=\u20090.046). <jats:italic>EGFR<\/jats:italic> rs2293348 and rs4947492 were associated with severe AEs (<jats:italic>p<\/jats:italic>\u2009=\u20090.019 and <jats:italic>p<\/jats:italic>\u2009=\u20090.050, respectively), and <jats:italic>ABCG2<\/jats:italic> rs2231137 and <jats:italic>ABCB1<\/jats:italic> rs1128503 were associated with grade\u2009\u2265\u20092 AEs (<jats:italic>p<\/jats:italic>\u2009=\u20090.008 and <jats:italic>p<\/jats:italic>\u2009=\u20090.038, respectively). <jats:bold>Conclusion:<\/jats:bold> Higher exposures to osimertinib, AZ5104, and AZ7550 and polymorphisms in <jats:italic>EGFR<\/jats:italic>, <jats:italic>ABCG2<\/jats:italic>, and <jats:italic>ABCB1<\/jats:italic> were related to higher severity of AEs; therefore, monitoring these may be beneficial for osimertinib AE management.<\/jats:p>","DOI":"10.1007\/s10637-023-01328-9","type":"journal-article","created":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T12:05:00Z","timestamp":1673611500000},"page":"122-133","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Population Pharmacokinetics, Pharmacogenomics, and Adverse Events of Osimertinib and its Two Active Metabolites, AZ5104 and AZ7550, in Japanese Patients with Advanced Non-small Cell Lung Cancer: a Prospective Observational 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The study protocol was reviewed and approved by the ethics committees of the Ageo Central General Hospital (Approval No. 564), Keio University School of Medicine (Approval No. 20200098), and Keio University Faculty of Pharmacy (Approval No. 210118\u20133 and 200710\u20131).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Written informed consent for the publication of their data was obtained from all the patients who participated in this study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}},{"value":"Dr. Hiroyuki Yasuda has received speaker honoraria from AstraZeneca, Brisol Meyers, and Ono, outside of the submitted work. Dr. Hitoshi Kawazoe has obtained a grant from Eli Lilly, outside of the submitted work. Dr. Kenzo Soejima has received grants from Taiho Pharmaceutical, Boehringer Ingelheim, and AstraZeneca, and speaker honoraria from Chugai, Ono Pharmaceutical, AstraZeneca, BMS, MSD, Takeda Pharmaceutical, Kyorin Pharmaceutical, Boehringer Ingelheim, Sanofi, Novartis, Eli Lilly, and Taiho Pharmaceutical, outside of the submitted work. Dr. Tomonori Nakamura has obtained grants from Astellas Pharma, Chugai, Daiichi Sankyo, Kyowa Kirin, Otsuka Pharmaceutical, Sanofi, Shionogi, and Sato Pharmaceutical, outside of the submitted work. The other authors have no relevant financial or non-financial interests to disclose.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}