Individualized dosing of direct oral anticoagulants using blood drug concentration

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K18930
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: University 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
• 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

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.

Free Research Field

治療薬物モニタリング、生理学的薬物速度論モデリング、薬理遺伝学

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。