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Individualized dosing of direct oral anticoagulants using blood drug concentration

Research Project

Project/Area Number 16K18930
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Medical pharmacy
Research InstitutionUniversity of Tsukuba

Principal Investigator

Doki Kosuke  筑波大学, 医学医療系, 講師 (90620881)

Research Collaborator Homma Masato  筑波大学, 医学医療系, 教授
Aonuma Kazutaka  筑波大学, 医学医療系, 教授
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsダビガトラン / 血中濃度 / 薬物相互作用 / 腎障害 / 生理学的薬物速度論モデリング / 生理学的速度論モデル / P-糖蛋白阻害薬 / 腎機能障害 / 直接作用型経口抗凝固薬 / 新規経口抗凝固薬 / 薬学
Outline of Final Research Achievements

Dabigatran etexilate (DABE) is an oral anticoagulant, and its excessive anticoagulant effect leads to increase a risk of bleeding. Plasma concentrations of dabigatran, an active moiety of DABE, are increased by renal impairment (RI) or coadministration of a P-glycoprotein (P-gp) inhibitor. Dose reduction from 150 mg b.i.d. to 110 mg b.i.d. is recommended when the patients have either risk factor, moderate RI or co-administration of P-gp inhibitors. The combined effects of drug-drug interactions (DDIs) and RI have not been evaluated by means of clinical studies. Among patients with co-administration of P-gp inhibitors, activated partial thromboplastin time was significantly prolonged in moderate RI patients than that in healthy group. Physiologically based pharmacokinetic modeling for DABE revealed that the moderate RI population required a further dose reduction (75 mg b.i.d.) to decrease the risk of major bleeding when coadministered with multiple verapamil doses.

Academic Significance and Societal Importance of the Research Achievements

医薬品開発における臨床試験では、腎障害患者における薬物相互作用のような複雑な使用条件をすべて評価するのは困難である。本研究では、実臨床における使用実態および生理学的薬物速度論モデルを用いた血中薬物濃度予測を用いて複雑な使用条件における薬物の適正な投与量を明らかにした。本研究の手法は他の薬物においても医薬品適正使用に有用であると考えられる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (6 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (2 results) Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (3 results) (of which Int'l Joint Research: 1 results)

  • [Int'l Joint Research] University of Manchester/Certara UK Ltd., Simcyp(英国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] University of Manchester/Certara UK Ltd., Simcyp Division(英国)

    • Related Report
      2017 Research-status Report
  • [Journal Article] Assessing Potential Drug-Drug Interactions Between Dabigatran Etexilate and a P-Glycoprotein Inhibitor in Renal Impairment Populations Using Physiologically Based Pharmacokinetic Modeling2019

    • Author(s)
      Doki Kosuke、Neuhoff Sibylle、Rostami-Hodjegan Amin、Homma Masato
    • Journal Title

      CPT: Pharmacometrics & Systems Pharmacology

      Volume: 8 Issue: 2 Pages: 118-126

    • DOI

      10.1002/psp4.12382

    • NAID

      120007128064

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Virtual drug-drug interaction study between dabigatran etexilate and a P-glycoprotein inhibitor in renal impairment population using physiologically-based pharmacokinetic modelling2018

    • Author(s)
      Kosuke Doki, Sibylle Neuhoff, Amin Rostami-Hodjegan, Masato Homma
    • Organizer
      2018 International Meeting on 22nd MDO and 33rd JSSX
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] P-糖蛋白阻害薬とダビガトラン併用患者における血液凝固能と腎機能の関係(第2報)2017

    • Author(s)
      横田裕之, 土岐浩介, 青沼和隆, 本間真人
    • Organizer
      第38回日本臨床薬理学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] Effects of kidney function on anticoagulant effect of dabigatran in patients with co-administration of P-glycoprotein inhibitors2016

    • Author(s)
      Hiroyuki Yokota, Kosuke Doki, Kazutaka Aonuma, Masato Homma
    • Organizer
      第10回次世代を担う若手医療薬科学シンポジウム
    • Place of Presentation
      群馬大学昭和キャンパス(群馬県前橋市)
    • Year and Date
      2016-11-05
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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