Development of the treatment strategy for molecular target anticancer drugs to avoid serious side effects

• Project/Area Number: 20K07150
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Akita University
• Principal Investigator: MIURA MASATOMO 秋田大学, 医学系研究科, 教授 (30265194)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 分子標的治療薬 / 血中濃度 / 遺伝子多型 / バイオマーカー / 個別化治療 / 副作用

Outline of Research at the Start

白血病治療薬ポナチニブ、甲状腺がん治療薬レンバチニブ、肺がん治療薬オシメルチニブは重篤な副作用発現による死亡例が報告されており、分子標的抗がん剤の中でもさらにハイリスクに位置付けられる。本研究ではこれら分子標的抗がん剤のターゲット血中濃度を算出し、その血中濃度をマーカーにした治療戦略を確立する。さらに副次評価項目として、各薬剤の特徴的な副作用発現のバイオマーカーを探索し血中濃度との相関性の検討と、ファーマコゲノミクス導入による初回投与設計が可能か、血中濃度の個人差を解明する目的で薬物動態関連遺伝子多型を解析する。本研究は治療開始後のプレシジョンメディスンを実臨床に導入させるための臨床研究である

Outline of Final Research Achievements

There was no significant difference in the plasma concentration of ponatinib among genotypes of ABCB1 or ABCG2 421C>A transporters; however, patients with SNPs associated with low P-glycoprotein activity had significantly higher cerebrospinal fluid-to-plasma ratios of ponatinib. There were no significant differences in the osimertinib AUC between genotypes of CYP3A4/5 or ABC transporters. Furthermore, there were no significant differences in the osimertinib AUC between patients with diarrhea, skin rash, or hepatotoxicity and those without these conditions. In multivariate analysis, only serum albumin value was an independent factor predicting the osimertinib AUC. In patients with partial response and stable disease for lenvatinib therapy, angiopoietin-2 (Ang-2) at 1 month were significantly lower than Ang-2 at baseline. The change of Ang-2 at 1 month from baseline may be important as a biomarker of the inhibitory effect of angiogenesis by lenvatinib.

Academic Significance and Societal Importance of the Research Achievements

日本人にとって添付文書記載の投与量は高用量であることが多く、治療開始早期で治療継続が困難となるケースが散見される。分子標的治療薬の効果や副作用は血中濃度と相関することが知られているため、治療開始後早期に血中濃度を測定し投与量を調節することで、重篤な副作用の回避、支持療法による医薬品使用の回避、さらに高額な医薬品費抑制に繋がる。血中濃度や遺伝子多型解析による個別化は患者に利益をもたらすと考えられる。

Research Products

• [Journal Article] Effects of ABCB1 polymorphisms on the transport of ponatinib into the cerebrospinal fluid in Japanese Philadelphia chromosome-positive acute lymphoblastic leukaemia patients. (2023)
  • Author(s): Fukushi Y, Akamine Y, Abumiya M, Tozawa N, Yamashita T, Nara M, Kameoka Y, Takahashi N, Miura M.
  • Journal Title: Br J Clin Pharmacol. Volume: 89(5) Issue: 5 Pages: 1695-1700
  • DOI: 10.1111/bcp.15650
  • Peer Reviewed
• [Journal Article] Effects of CYP3A4/5 and ABC transporter polymorphisms on osimertinib plasma concentrations in Japanese patients with non-small cell lung cancer (2022)
  • Author(s): Yokota Hayato、Sato Kazuhiro、Sakamoto Sho、Okuda Yuji、Fukuda Natsuki、Asano Mariko、Takeda Masahide、Nakayama Katsutoshi、Miura Masatomo
  • Journal Title: Investigational New Drugs Volume: 40 Issue: 6 Pages: 1254-1262
  • DOI: 10.1007/s10637-022-01304-9
  • Peer Reviewed / Open Access
• [Journal Article] Associations Between Plasma Concentrations of Lenvatinib and Angiopoietin and Clinical Responses to Lenvatinib Therapy in Japanese Patients With Thyroid Cancer (2022)
  • Author(s): Kumagai M, Nagahama M, Akamine Y, Ozeki T, Suzuki A, Sugino K, Ito K, Miura M.
  • Journal Title: Cancer Diagn Progn Volume: 2(3) Issue: 3 Pages: 336-344
  • DOI: 10.21873/cdp.10114
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between achievement of major molecular response or deep molecular response and nilotinib plasma concentration in patients with chronic myeloid leukemia receiving first-line nilotinib therapy (2022)
  • Author(s): Fukuda N, Akamine Y, Abumiya M, Takahashi S, Yoshioka T, Kameoka Y, Takahashi N, Miura M.
  • Journal Title: Cancer Chemother Pharmacol Volume: 89(5) Issue: 5 Pages: 609-616
  • DOI: 10.1007/s00280-022-04419-1
  • Peer Reviewed
• [Journal Article] Association between ABCC2 polymorphism and hematological toxicity in patients with esophageal cancer receiving platinum plus 5-fluorouracil therapy (2022)
  • Author(s): Fujita K, Motoyama S, Sato Y, Wakita A, Nagaki Y, Minamiya Y, Miura M.
  • Journal Title: Esophagus. Volume: 19 Issue: 1 Pages: 146-152
  • DOI: 10.1007/s10388-021-00865-7
  • NAID: 40022800671
  • Peer Reviewed
• [Journal Article] Evaluation of the plasma concentration of ponatinib in a chronic myeloid leukaemia patient with ponatinib intolerance (2021)
  • Author(s): Abumiya M, Takahashi N, Yoshioka T, Kameoka Y, Miura M
  • Journal Title: J Clin Pharm Ther Volume: 46 Issue: 1 Pages: 219-222
  • DOI: 10.1111/jcpt.13257
  • Peer Reviewed
• [Journal Article] The BCRP inhibitor febuxostat enhances the effect of nilotinib by regulation of intracellular concentration (2021)
  • Author(s): Ito F, Miura M, Fujioka Y, Abumiya M, Kobayashi T, Takahashi S, Yoshioka T, Kameoka Y, Takahashi N.
  • Journal Title: Int J Hematol Volume: 113 Issue: 1 Pages: 100-105
  • DOI: 10.1007/s12185-020-03000-x
  • Peer Reviewed
• [Journal Article] Effects of proprotein convertase subtilisin/kexin type 9 and nilotinib plasma concentrations on nilotinib-induced hypercholesterolemia in patients with chronic myeloid leukemia (2021)
  • Author(s): Abumiya M, Akamine Y, Sato S, Takahashi S, Yoshioka T, Kameoka Y, Takahashi N, Miura M.
  • Journal Title: J Clin Pharm Ther Volume: 46 Issue: 2 Pages: 382-387
  • DOI: 10.1111/jcpt.13294
  • Peer Reviewed
• [Journal Article] Effects of SLC31A1 and ATP7B polymorphisms on platinum resistance in patients with esophageal squamous cell carcinoma receiving neoadjuvant chemoradiotherapy (2021)
  • Author(s): Fujita Kazuma、Motoyama Satoru、Sato Yusuke、Wakita Akiyuki、Nagaki Yushi、Minamiya Yoshihiro、Miura Masatomo
  • Journal Title: Medical Oncology Volume: 38 Issue: 1 Pages: 6-6
  • DOI: 10.1007/s12032-020-01450-1
  • Peer Reviewed
• [Journal Article] Effects of SLC22A2 808G>T polymorphism and bosutinib concentrations on serum creatinine in patients with chronic myeloid leukemia receiving bosutinib therapy (2021)
  • Author(s): Abumiya M, Takahashi N, Takahashi S, Yoshioka T, Kameoka Y, Miura M.
  • Journal Title: Sci Rep Volume: 11 Issue: 1 Pages: 6362-6362
  • DOI: 10.1038/s41598-021-85757-7
  • NAID: 120007172092
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and safety of ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: a case series from a single institute (2021)
  • Author(s): Kidoguchi K, Ureshino H, Kizuka-Sano H, Yamaguchi K, Katsuya H, Kubota Y, Ando T, Miura M, Takahashi N, Kimura S.
  • Journal Title: Int J Hematol. Volume: 114 Issue: 2 Pages: 199-204
  • DOI: 10.1007/s12185-021-03156-0
  • Peer Reviewed
• [Journal Article] Serial evaluation of the pharmacokinetics of ponatinib in patients with CML and Ph + ALL (2021)
  • Author(s): Kawano N, Kimura S, Miura M, Tochigi T, Nakaike T, Yamashita K, Mashiba K, Kikuchi I, Takahashi N.
  • Journal Title: Int J Hematol. Volume: 114 Issue: 4 Pages: 509-516
  • DOI: 10.1007/s12185-021-03186-8
  • Peer Reviewed
• [Journal Article] Relationship between Plasma Concentrations of Afatinib and the Onset of Diarrhea in Patients with Non-Small Cell Lung Cancer (2021)
  • Author(s): Yokota Hayato、Sato Kazuhiro、Sakamoto Sho、Okuda Yuji、Asano Mariko、Takeda Masahide、Nakayama Katsutoshi、Miura Masatomo
  • Journal Title: Biology Volume: 10 Issue: 10 Pages: 1054-1054
  • DOI: 10.3390/biology10101054
  • NAID: 120007172095
  • Peer Reviewed / Open Access
• [Journal Article] Low-dose dasatinib in older patients with chronic myeloid leukaemia in chronic phase (DAVLEC): a single-arm, multicentre, phase 2 trial (2021)
  • Author(s): Murai K, Ureshino H, Kumagai T, Tanaka H, Nishiwaki K, Wakita S, Inokuchi K, Fukushima T, Yoshida C, Uoshima N, Kiguchi T, Mita M, Aoki J, Kimura S, Karimata K, Usuki K, Shimono J, Chinen Y, Kuroda J, Matsuda Y, Nakao K, Ono T, Fujimaki K, Shibayama H, Sakamoto J, Kimura S.
  • Journal Title: Lancet Haematol Volume: 8 Issue: 12 Pages: e902-e911
  • DOI: 10.1016/s2352-3026(21)00333-1
  • Peer Reviewed / Open Access
• [Journal Article] Regulatory T Cell as a Biomarker of Treatment-Free Remission in Patients with Chronic Myeloid Leukemia (2021)
  • Author(s): Fujioka Y, Sugiyama D, Matsumura I, Minami Y, Miura M, Atsuta Y, Ohtake S, Kiyoi H, Miyazaki Y, Nishikawa H, Takahashi N
  • Journal Title: Cancers Volume: 13 Issue: 23 Pages: 5904-5904
  • DOI: 10.3390/cancers13235904
  • Peer Reviewed / Open Access
• [Journal Article] The Impact of Hemodialysis and Liver Cirrhosis on the Plasma Concentrations of Tyrosine Kinase Inhibitors in a Patient with Chronic Myeloid Leukemia (2020)
  • Author(s): Taniguchi Y, Takahashi N, Miura M, Hirase C, Sueda S, Espinoza JL, Rai S, Nakayama S, Serizawa K, Kumode T, Watatani Y, Morita Y, Tanaka H, Matsumura I.
  • Journal Title: Internal Medicine Volume: 59 Issue: 21 Pages: 2745-2749
  • DOI: 10.2169/internalmedicine.4871-20
  • NAID: 130007934222
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-11-01
  • Peer Reviewed / Open Access
• [Journal Article] 新規TDM対象薬への対応と展望 (2020)
  • Author(s): 三浦昌朋
  • Journal Title: 日本病院薬剤師会雑誌 Volume: 56 Pages: 977-981
  • NAID: 40022351637
  • Peer Reviewed
• [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] 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
• [Presentation] 分子標的治療薬のHPLC法を用いた定量とTDMの臨床実装 (2022)
  • Author(s): 三浦昌朋
  • Organizer: 第38回日本TDM学会・学術大会
• [Presentation] 血漿濃度を用いたオシメルチニブ治療の多施設前向き観察研究 (2022)
  • Author(s): 井草龍太郎，福原達朗，今井一博，中川 拓，横田隼人，渡邉香奈，鈴木 綾，盛田麻美，井上 彰，三浦昌朋，南谷佳弘，前門戸任
  • Organizer: 第62回日本呼吸器学会学術講演会
• [Presentation] 非小細胞肺がんにおけるアファチニブ血中濃度と副作用と関係 (2022)
  • Author(s): 横田隼人，佐藤一洋，坂本 祥，奥田佑道，浅野真理子，竹田正秀，中山勝敏，三浦昌朋
  • Organizer: 第32回日本医療薬学会年会
• [Presentation] Dasatinib Is a Safe and Effective Therapy for Elderly Patients with Newly-Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Results from the Davlec Study, a Single-Arm, Multicenter, Phase 2 Trial (2021)
  • Author(s): Kumagai T, Murai K, Ureshino H, Tanaka H, Nishiwaki K, Wakita S, Inokuchi K, Fukushima T, Yoshida C, Mita M, Uoshima N, Kiguchi T, Aoki J, Kimura S, Karimata K, Usuki K, Shimono J, Chinen Y, Kuroda J, Matsuda Y, Nakao K, Ono T, Fujimaki K, Shibayama H, Mizumoto C, Takeoka T, Io K, Kondo T, Miura M, et al.
  • Organizer: 63rd ASH Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] A prospective observational study of osimertinib using plasma concentrations in NSCLC with acquired EGFR T790M mutation (2021)
  • Author(s): Nakagawa T, Fukuhara T, Imai K, Igusa R, Yokota H, Watanabe K, Suzuki A, Morita M, Inoue A, Miura M, Minamiya Y, Maemondo M
  • Organizer: 2021 World Conference on Lung Cancer
  • Int'l Joint Research
• [Presentation] Gefitinibの血中濃度と薬物動態に関する遺伝子多型との関係性についての検討 (2021)
  • Author(s): 坂本 祥, 佐藤一洋, 横田隼人, 赤嶺由美子, 奥田佑道, 浅野真理子, 竹田正秀, 三浦昌朋, 中山勝敏
  • Organizer: 第61回日本呼吸器学会学術講演会
• [Presentation] 進行大腸がん患者におけるレゴラフェニブの血中濃度と治療効果の関連 (2021)
  • Author(s): 野田哲史，土手賢史，石塚保亘，寺澤哲志，後藤愛実，高橋克之，佐野村誠，谷 眞至，安藤 朗，三浦昌朋，後藤昌弘，寺田智祐
  • Organizer: 医療薬学フォーラム2021/第29回クリニカルファーマシーシンポジウム
• [Presentation] Effect of SLC22A2 SNP and bosutinib concentrations on serum creatinine in patients taking bosutinib (2021)
  • Author(s): Abumiya M, Takahashi N, Takahashi S, Yoshioka T, Kameoka, Y, Miura M
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] オシメルチニブ治療における血漿濃度測定の有用性を検討する前向き観察研究 (2021)
  • Author(s): 今井一博，福原達朗，中川 拓，井草龍太郎，横田隼人，渡邉香奈，鈴木 綾，盛田麻美，井上 彰，三浦昌朋，南谷佳弘，前門戸任
  • Organizer: 第62回日本肺癌学会学術集会
• [Presentation] 薬物投与設計時に必要な医療技術の充実化を目指して (2020)
  • Author(s): 三浦昌朋
  • Organizer: 第30回医療薬学会年会