Development of the treatment strategy for molecular target anticancer drugs to avoid serious side effects
Project/Area Number |
20K07150
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 47060:Clinical pharmacy-related
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Research Institution | Akita University |
Principal Investigator |
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Project Period (FY) |
2020-04-01 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥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)
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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
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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.
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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。
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Report
(4 results)
Research Products
(29 results)
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[Journal Article] Low-dose dasatinib in older patients with chronic myeloid leukaemia in chronic phase (DAVLEC): a single-arm, multicentre, phase 2 trial2021
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.
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Journal Title
Lancet Haematol
Volume: 8
Issue: 12
Pages: e902-e911
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Regulatory T Cell as a Biomarker of Treatment-Free Remission in Patients with Chronic Myeloid Leukemia2021
Author(s)
Fujioka Y, Sugiyama D, Matsumura I, Minami Y, Miura M, Atsuta Y, Ohtake S, Kiyoi H, Miyazaki Y, Nishikawa H, Takahashi N
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Journal Title
Cancers
Volume: 13
Issue: 23
Pages: 5904-5904
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] The Impact of Hemodialysis and Liver Cirrhosis on the Plasma Concentrations of Tyrosine Kinase Inhibitors in a Patient with Chronic Myeloid Leukemia2020
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.
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Journal Title
Internal Medicine
Volume: 59
Issue: 21
Pages: 2745-2749
DOI
NAID
ISSN
0918-2918, 1349-7235
Year and Date
2020-11-01
Related Report
Peer Reviewed / Open Access
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[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 Trial2021
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
Related Report
Int'l Joint Research
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[Presentation] A prospective observational study of osimertinib using plasma concentrations in NSCLC with acquired EGFR T790M mutation2021
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
Related Report
Int'l Joint Research
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