Establishment of systems-based prediction method for drug adverse effects.

• Project/Area Number: 24249034
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: The University of Tokyo
• Principal Investigator: Suzuki Hiroshi 東京大学, 医学部附属病院, 教授 (80206523)
• Co-Investigator(Kenkyū-buntansha): HONMA Masashi 東京大学, 医学部附属病院, 特任准教授 (60401072)
• Project Period (FY): 2012-10-31 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥43,680,000 (Direct Cost: ¥33,600,000、Indirect Cost: ¥10,080,000); Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000); Fiscal Year 2013: ¥11,440,000 (Direct Cost: ¥8,800,000、Indirect Cost: ¥2,640,000); Fiscal Year 2012: ¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000)
• Keywords: 薬剤反応性 / 薬理学 / シミュレーション

Outline of Final Research Achievements

We aimed to develop the systems-based prediction method for drug adverse reactions. In the present study, we focused on drug cardiotoxicity and constructed a comprehensive systmes-biological model of cardiomyocyte proliferation and apoptosis. We also developed a novel method to determine the allowable parameter ranges for the network behavior to satisfy some constraints, which reflects the features of cell proliferation and apoptosis. Application of this novel analysis method to the comprehensive cardiomyocyte model provided better prediction of cardiotoxicity compared to the conventional method using static network analysis.

Research Products

• [Journal Article] Mechanism analyses and mechanism-based prediction for adverse drug reactions using systems pharmacology (2016)
  • Author(s): Kariya Y, Honma M, Suzuki H.
  • Journal Title: Folia Pharmacologica Japonica Volume: 147 Issue: 2 Pages: 89-94
  • DOI: 10.1254/fpj.147.89
  • NAID: 130005125653
  • ISSN: 0015-5691, 1347-8397
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Elucidation of the molecular mechanisms underlying adverse reactions associated with a kinase inhibitor using systems toxicology. (2015)
  • Author(s): Takahiro Amemiya, Masashi Honma, Yoshiaki Kariya, Samik Ghosh, Hiroaki Kitano, Yoshihisa Kurachi, Ken-ichi Fujita, Yasutsuna Sasaki, Yukio Homma, Darrel R Abernethy, Haruki Kume, Hiroshi Suzuki.
  • Journal Title: npj Systems Biology and Applications Volume: 1 Issue: 1 Pages: 1-10
  • DOI: 10.1038/npjsba.2015.5
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Systems-based understanding of pharmacological responses with combinations of multidisciplinary methodologies (2013)
  • Author(s): Yoshiaki Kariya, Masashi Honma, Hiroshi Suzuki
  • Journal Title: Biopharmaceutics & Drug Disposition Volume: 34(9) Issue: 9 Pages: 489-507
  • DOI: 10.1002/bdd.1865
  • Peer Reviewed
• [Presentation] 細胞内シグナルネットワークを考慮したシステム薬理学的心毒性予測 (2016)
  • Author(s): 苅谷嘉顕、本間雅、鈴木洋史
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2016-03-18
• [Presentation] 薬物副作用に関するトランスレーショナル研究サイクル (2015)
  • Author(s): 本間雅
  • Organizer: 日本薬物動態学会第３０年会
  • Place of Presentation: 東京
  • Year and Date: 2015-11-12
  • Invited
• [Presentation] Prediction of tki associated cardiotoxicity based on network analyses of intracellular signaling pathways (2015)
  • Author(s): Yoshiaki Kariya, Masashi Honma, Hiroshi Suzuki
  • Organizer: Workshop on Pharmacological Mechanism-Based Drug Safety Prediction
  • Place of Presentation: Silver Spring, MD, USA
  • Year and Date: 2015-08-06
  • Int'l Joint Research
• [Presentation] Systems Pharmacology Approach to Tyrosine Kinase Inhibitor Toxicity (2015)
  • Author(s): Hiroshi Suzuki
  • Organizer: ASCPT2015 pre-conference
  • Place of Presentation: New Orleans
  • Year and Date: 2015-03-03
  • Invited
• [Presentation] Utilization of Systems-Biology in Analyzing and Predicting the Toxicity of Molecular Target Drugs (2014)
  • Author(s): Hiroshi Suzuki
  • Organizer: 19th North American ISSX Meeting / 29th JSSX Meeting
  • Place of Presentation: San Francisco
  • Year and Date: 2014-10-19 – 2014-10-23
  • Invited
• [Presentation] 医薬品適正使用から医薬品創成へ:分子標的薬を例として (2014)
  • Author(s): 本間雅
  • Organizer: 医療薬学フォーラム2014/第22回クリニカルファーマシーシンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2014-06-28 – 2014-06-29
  • Invited
• [Presentation] Pk-pd analysis of mechanism of toxicity of molecular target drugs: towards optimal treatment of cancer (2014)
  • Author(s): Hiroshi Suzuki
  • Organizer: 5th FIP Pharmaceutical Sciences World Congress
  • Place of Presentation: Melbourne
  • Year and Date: 2014-04-13 – 2014-04-16
  • Invited
• [Presentation] Systems-based understanding of TKI cardiotoxicity (2013)
  • Author(s): Masashi Honma
  • Organizer: 第28回日本薬物動態学会
  • Place of Presentation: 東京
  • Invited
• [Presentation] Challenges to clarify the mechanism of heart toxicity of sunitib based on systems-biological approach (2013)
  • Author(s): Hiroshi Suzuki
  • Organizer: Systems Pharmacology for the Prediction of Tyrosine Kinase (TKI workshop)
  • Place of Presentation: Silver Spring, MD, USA
  • Invited
• [Presentation] キナーゼ阻害薬による副作用発現機構の解析 (2012)
  • Author(s): 本間 雅
  • Organizer: 日本薬物動態学会 第２７回年会
  • Place of Presentation: 東京
  • Invited