Effects of pharmacokinetics on the clinical outcomes of gefitinib treatment in patients with EGFR-mutation positive non-small cell lung cancer

• Project/Area Number: 17K09602
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Akita University
• Principal Investigator: Sato Kazuhiro 秋田大学, 医学系研究科, 特任准教授 (30436191)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 個別化治療 / 肺癌 / 薬物動態 / 代謝酵素 / EGFR-TKI / 血中濃度 / トランスポーター / 遺伝子多型 / 非小細胞肺癌 / EGFR-TKI血中濃度 / 予後予測因子 / 分子標的治療

Outline of Final Research Achievements

ABCG2 is thought to inhibit the activities of certain gefitinib transporters, thereby affecting drug pharmacokinetics. The C421A polymorphism affects the function and expression of ABCG2 on the cell membrane. We evaluated the plasma concentrations of gefitinib in patients with and without the ABCG2 C421A polymorphism. Plasma gefitinib concentration and ABCG2 C421A status were determined. The patients were divided into CC- and CA/AA genotype groups. We compared the trough and peak gefitinib levels and the AUC values for 24-h gefitinib concentrations. The mean trough gefitinib level and AUC value for 24-h gefitinib concentration were significantly lower in the CA/AA group compared to the CC group. Among patients taking PPIs, the mean trough gefitinib level was significantly lower in the CA/AA group than the CC group. The CA/AA-type of ABCG2 C421A polymorphism may be associated with lower gefitinib plasma concentrations.

Academic Significance and Societal Importance of the Research Achievements

血中濃度を測定しターゲット濃度を継続させることで、1）副作用を未然に防止でき、2）無効域推移による無駄な時間とコストを削減でき、攻めの治療が実施できるはずである。本研究の特色は、TDMのみならず薬剤血中濃度を予測しうる遺伝子多型より、治療開始前から効果と有害事象を予測することある。それにより試行錯誤的治療を回避し、より早くターゲット血中濃度に到達させることで、効率良く治療を進めることができるようになる。本検討によってもたらされる治療戦略はいかに安全かつ効率的に治療を継続させるかであるが、そればかりか、高齢化社会を迎えるに当たり、高騰の一途をたどる薬剤費の抑制を図れる手段の一つともなりえる。

Research Products

• [Journal Article] ABCG2 C421A polymorphisms affect exposure of the epidermal growth factor receptor inhibitor gefitinib (2020)
  • Author(s): Sakamoto Sho、Sato Kazuhiro、Takita Yuri、Izumiya Yuka、Kumagai Naho、Sudo Kazuhisa、Hasegawa Yukiyasu、Yokota Hayato、Akamine Yumiko、Okuda Yuji、Asano Mariko、Takeda Masahide、Sano Masaaki、Miura Masatomo、Nakayama Katsutoshi
  • Journal Title: Investigational New Drugs Volume: 38 Issue: 6 Pages: 1687-1695
  • DOI: 10.1007/s10637-020-00946-x
  • Peer Reviewed / Open Access
• [Journal Article] Effects ofSTAT3polymorphisms and pharmacokinetics on the clinical outcomes of gefitinib treatment in patients with EGFR‐mutation positive non‐small cell lung cancer (2020)
  • Author(s): Yokota Hayato、Sato Kazuhiro、Sakamoto Sho、Okuda Yuji、Asano Mariko、Takeda Masahide、Nakayama Katsutoshi、Miura Masatomo
  • Journal Title: Journal of Clinical Pharmacy and Therapeutics Volume: 45 Issue: 4 Pages: 652-659
  • DOI: 10.1111/jcpt.13173
  • Peer Reviewed / Open Access
• [Journal Article] An autopsy case of anaplastic lymphoma kinase-positive lung cancer exacerbated in a short period of time: a case report (2019)
  • Author(s): Takeda Masahide、Sato Kazuhiro、Sakamoto Sho、Suzuki Maya、Izumiya Yuka、Kumagai Naho、Sudo Kazuhisa、Okuda Yuji、Asano Mariko、Sano Masaaki、Omori Yasufumi、Nakayama Katsutoshi
  • Journal Title: Journal of Medical Case Reports Volume: 13 Issue: 1 Pages: 118-118
  • DOI: 10.1186/s13256-019-2054-3
  • Peer Reviewed / Open Access
• [Journal Article] Blepharoptosis Due to Sarcoidosis-Induced Horner Syndrome (2019)
  • Author(s): Takeda Masahide、Sato Kazuhiro、Sano Masaaki、Sakamoto Sho、Izumiya Yuka、Kumagai Naho、Sudo Kazuhisa、Asano Mariko、Okuda Yuji、Nakayama Katsutoshi
  • Journal Title: American Journal of Respiratory and Critical Care Medicine Volume: 印刷中 Issue: 1 Pages: 101-102
  • DOI: 10.1164/rccm.201807-1285im
  • Peer Reviewed / Open Access
• [Journal Article] Mucus plugging in allergic bronchopulmonary aspergillosis: Implication of the eosinophil DNA traps (2018)
  • Author(s): Omokawa Ayumi、Ueki Shigeharu、Kikuchi Yuta、Takeda Masahide、Asano Mariko、Sato Kazuhiro、Sano Masaaki、Ito Hiroshi、Hirokawa Makoto
  • Journal Title: Allergology International Volume: 67 Issue: 2 Pages: 280-282
  • DOI: 10.1016/j.alit.2017.08.002
  • NAID: 130006721874
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Low plasma concentration of gefitinib in patients with EGFR exon 21 L858R point mutations shortens progression-free survival (2017)
  • Author(s): Okuda Yuji、Sato Kazuhiro、Sudo Kazuhisa、Hasegawa Yukiyasu、Asano Mariko、Miura Hajime、Takeda Masahide、Sano Masaaki、Watanabe Hiroyuki、Kobayashi Hiroyuki、Niioka Takenori、Miura Masatomo、Ito Hiroshi
  • Journal Title: Cancer Chemotherapy and Pharmacology Volume: 79 Issue: 5 Pages: 1013-1020
  • DOI: 10.1007/s00280-017-3285-x
  • Peer Reviewed
• [Journal Article] Association Between Endothelial Progenitor Cells and Treatment Response in Non-Squamous Non-small Cell Lung Cancer Treated with Bevacizumab (2017)
  • Author(s): KAZUHISA SUDO, KAZUHIRO SATO, SHO SAKAMOTO, YUKIYASU HASEGAWA, MARIKO ASANO, YUJI OKUDA, MASAHIDE TAKEDA, MASAAKI SANO, HIROYUKI WATANABE, TAKANOBU SHIOYA , HIROSHI ITO
  • Journal Title: Anticancer Research Volume: 37 Issue: 10 Pages: 5565-5571
  • DOI: 10.21873/anticanres.11989
  • Peer Reviewed
• [Presentation] Association between proton-pump inhibitors and the ABCG2 C421A polymorphism and plasma concentration of gefitinib (2021)
  • Author(s): Sakamoto,S.,Sato,K.,Goshima,S.,Asahi,R.,Takita,Y.,Omoto,E.,Izumiya,Y.,Kumagai,N.,Hasegawa,Y.,Yokota,H.,Okuda,Y.,Asano,M.,Akamine,Y.,Takeda,M.,Miura,M. and Nakayama,K.
  • Organizer: The 25th Congress of the Asian Pacific Society of Respirology
  • Int'l Joint Research
• [Presentation] Effect of the ABCG2 C421A Polymorphism on Plasma Concentration of Gefitinib. (2019)
  • Author(s): S.Sakamoto, K.Sato, Y.Okuda, Y.Izumia, N.Kumagai, K.Sudo, M.Asano, M.Takeda, M.Sano, K.Nakayama.
  • Organizer: American Thoracic Society
• [Presentation] 気道上皮細胞からのサイトカイン産生、粘液産生におけるPhosphoinositide 3-kinaseの関わり (2019)
  • Author(s): 竹田正秀，佐藤一洋，植木重治，丹 典子，泉谷有可，熊谷奈保，坂本 祥，須藤和久，長谷川幸保，浅野真理子，奥田佑道，佐野正明，中山勝敏
  • Organizer: 日本呼吸器学会学術講演会
• [Presentation] gefitinbの薬物動態と血中濃度の変動に関する検討 (2019)
  • Author(s): 中山勝敏，坂本 祥，佐藤一洋，奥田佑道，浅野真理子，板倉有紀，大田秀隆，横田隼人，赤嶺由美子，三浦昌朋
  • Organizer: 日本老年医学会学術集会
• [Presentation] in vitroにおけるシャルコー・ライデン結晶の形成機構 (2019)
  • Author(s): 竹田正秀，植木重治，福地峰世，宮部 結，面川 歩，嵯峨知生，守時由起，佐藤一洋，佐野正明，中山勝敏，廣川 誠
  • Organizer: 日本アレルギー学会学術大会
• [Presentation] 気道上皮細胞株からのサイトカイン産生および粘液産生機構におけるPhosphoinositide 3-kinaseγの関与 (2019)
  • Author(s): 竹田正秀，佐藤一洋，植木重治，丹 典子，泉谷有可，熊谷奈保，坂本 祥，須藤和久，長谷川幸保，浅野真理子，奥田佑道，佐野正明，中山勝敏
  • Organizer: 日本呼吸器学会学術講演会
• [Presentation] 気管原発小細胞癌の一例 (2019)
  • Author(s): 坂本 祥，佐藤一洋，泉谷有可，熊谷奈保，須藤和久，浅野真理子，奥田佑道，竹田正秀，佐野正明，中山勝敏
  • Organizer: 日本呼吸器学会東北地方会
• [Presentation] 低Na血症を合併した播種性Cryptococcus感染症の一例 (2019)
  • Author(s): 泉谷有可，佐藤一洋，坂本 祥，熊谷奈保，須藤和久，浅野真理子，奥田佑道，竹田正秀，佐野正明，中山勝敏
  • Organizer: 日本呼吸器学会東北地方会
• [Presentation] mesalazineによる器質化肺炎が疑われた一例 (2019)
  • Author(s): 坂本 祥，泉谷有可，熊谷奈保，須藤和久，長谷川幸保，浅野真理子，奥田佑道，竹田正秀，佐藤一洋，三浦一樹，中山勝敏
  • Organizer: 日本呼吸器学会東北地方会
• [Presentation] ペンブロリズマブによる腸炎を契機にLemmel症候群を発症した1例 (2019)
  • Author(s): 熊谷奈保，浅野真理子，泉谷有可，坂本 祥，須藤和久，長谷川幸保，奥田佑道，竹田正秀，佐藤一洋，本間光信，中山勝敏
  • Organizer: 日本呼吸器学会東北地方会
• [Presentation] 気道上皮細胞株からのサイトカイン産生および粘液産生機構におけるPhosphoinositide 3-kinase γの関与 (2019)
  • Author(s): 竹田正秀、佐藤一洋、植木重治、丹典子、泉谷有可、熊谷奈保、坂本祥、須藤和久、長谷川幸保、浅野真理子、奥田佑道、佐野正明、中山勝敏
  • Organizer: 第1回日本アレルギー学会東北地方会
• [Presentation] 気道上皮細胞からのサイトカイン産生、粘液産生におけるPhosphoinositide 3-kinase γの関 (2019)
  • Author(s): 竹田正秀、佐藤一洋、植木重治、丹典子、泉谷有可、熊谷奈保、坂本祥、須藤和久、長谷川幸保、浅野真理子、奥田佑道、佐野正明、中山勝敏
  • Organizer: 第59回日本呼吸器学会学術講演会
• [Presentation] ABCG2 C421A遺伝子多型とPPI併用によるgefitinibの血中濃度の変動に関する検討 (2018)
  • Author(s): 坂本祥、佐藤一洋、奥田佑道、横田隼人、赤嶺由美子、泉谷有可、熊谷奈保、須藤和久、長谷川幸保、浅野真理子、竹田正秀、佐野正明、三浦昌朋、中山勝敏
  • Organizer: 第59回日本肺癌学会学術集会