Construction and evaluation of a mechanism-based dynamic PK/PD model for antimicrobial agents for clinical application

• Project/Area Number: 20K07127
• 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: The University of Tokyo
• Principal Investigator: Yamamoto Takehito 東京大学, 大学院薬学系研究科(薬学部), 講師 (00376469)
• 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: PK/PD理論 / 数理モデル / 抗菌薬 / モデル解析 / シミュレーション / PKPD理論 / 動的PK/PDモデル

Outline of Research at the Start

抗菌薬を投与する際は、薬物動態学・薬力学理論に基づく合理的な投与設計が必要であるが、その基本となる理論は腎機能正常患者を前提に構築されている。本研究では、薬物血中濃度や抗菌薬の細菌に対する作用メカニズムを数理モデルに基づいて解析することで、これらの基本理論を腎不全患者にも拡張可能とすることを目的とする。本研究の完成により、これまでは困難であった重度腎障害患者など、薬物体内動態が大きく変動した患者に対する論理的な投与設計が可能となることが期待される。

Outline of Final Research Achievements

Bottom-up approach for estimation of pharmacokinetic/pharmacodynamic (PK/PD) indices of antimicrobial agents from basic PK and PD parameters have not yet been established. The aim of this study is to develop a methodology to describe the PK/PD indices of antimicrobial agents as a function of basic PK and PD parameters to enable the estimation of optimal PK/PD indices in patients with various clinical conditions.
We constructed dynamic PK/PD models that incorporates the in vitro bactericidal parameters of each antimicrobial agent and conducted a numerical simulation using the population PK parameters of each antimicrobial agent to verify whether the dynamic PK/PD models can estimate clinically established PK/PD indices.

Academic Significance and Societal Importance of the Research Achievements

研究期間内に得られた知見を基に本研究を更に発展させることにより、PKパラメーターおよびin vitro殺菌作用パターンより得らえるPDパラメーターから様々な疾患状態にある患者において抗菌薬の臨床効果をシミュレーションすることが可能となると考えられる。これまでは困難であった重度腎障害患者や血液透析導入患者など、薬物体内動態が大きく変動した患者に対するPK/PD理論に基づいた論理的な投与設計が可能となることが期待される。

Research Products

• [Journal Article] Teicoplanin and vancomycin as treatment for glycopeptide-susceptible Enterococcus faecium bacteraemia: a propensity score-adjusted non-inferior comparative study (2023)
  • Author(s): Ryo Yamaguchi, Takehito Yamamoto, Koh Okamoto, Sohei Harada, Miho Echizenya, Takeya Tsutsumi, Tappei Takada
  • Journal Title: Journal of Antimicrobial Chemotherapy Volume: - Issue: 5 Pages: 1231-1240
  • DOI: 10.1093/jac/dkad079
  • Peer Reviewed / Open Access
• [Journal Article] Impact of targeted intervention using a collaborative approach for oral third-generation cephalosporins: An interrupted time-series analysis (2022)
  • Author(s): Ryo Yamaguchi, Koh Okamoto, Takehito Yamamoto, Sohei Harada, Takehiro Tanaka, Hiroshi Suzuki, Kyoji Moriya
  • Journal Title: Antimicrobial Stewardship & Healthcare Epidemiology Volume: 2 Issue: 1
  • DOI: 10.1017/ash.2022.251
  • Peer Reviewed / Open Access
• [Journal Article] Prospective audit and feedback implementation by a multidisciplinary antimicrobial stewardship team shortens the time to de-escalation of anti-MRSA agents (2022)
  • Author(s): Ryo Yamaguchi, Takehito Yamamoto, Koh Okamoto, Keita Tatsuno, Mahoko Ikeda, Takehiro Tanaka, Yoshitaka Wakabayashi, Tomoaki Sato, Shu Okugawa, Kyoji Moriya, Hiroshi Suzuki
  • Journal Title: PLoS One Volume: 17 Issue: 7 Pages: e0271812-e0271812
  • DOI: 10.1371/journal.pone.0271812
  • Peer Reviewed / Open Access
• [Journal Article] History of whole pelvis plus para-aortic radiation is a risk factor associated with febrile neutropenia during chemotherapy for recurrent cervical cancer (2021)
  • Author(s): Nara Katsuhiko、Taguchi Ayumi、Tojima Yuri、Miyamoto Yuichiro、Tanikawa Michihiro、Sone Kenbun、Mori Mayuyo、Tsuruga Tetsushi、Yamamoto Takehito、Takenaka Ryosuke、Takada Tappei、Osuga Yutaka、Suzuki Hiroshi
  • Journal Title: International Journal of Clinical Oncology Volume: 26 Issue: 9 Pages: 1759-1766
  • DOI: 10.1007/s10147-021-01950-8
  • Peer Reviewed / Open Access