Elucidation of pharmacokinetic variability of activated factor X inhibitor for individualized pharmacotherapy
| Project/Area Number |
19K07234
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 47060:Clinical pharmacy-related
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| Research Institution | Ritsumeikan University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 第Xa因子阻害薬 / 薬物動態 / 母集団薬物速度論 / 薬理ゲノム解析 / 生理学的薬物速度論 / 個別化投与設計 / 薬理遺伝学 / 生物学的薬物速度論 / 医療薬剤学 |
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| Outline of Research at the Start |
心原性脳塞栓症の予防に使用される第Xa因子阻害薬は、添付文書に記載されている用法・用量に準じて投与しても出血症状が高頻度で認められること、薬効や出血症状を反映する指標が確立されていないことが問題になっている。第Xa因子阻害薬の血中濃度が薬効や出血症状に深く関係することから、第Xa因子阻害薬の体内動態の制御機構を明らかにすることは、薬物療法の最適化を図る上で重要である。本研究目的は、第Xa因子阻害薬の体内動態の制御機構と体内動態に対する組織の寄与を薬物速度論的手法や母集団薬物速度論的手法、薬物動態関連遺伝子解析により解明することである。
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| Outline of Final Research Achievements |
Apixaban and rivaroxaban, oral direct inhibitors of activated coagulation factor X, are used to prevent stroke or systemic embolism in patients. This study aimed to evaluate the impact of characteristics of patients and genetic variants in drug transporters and enzyme on the pharmacokinetics of apixaban and rivaroxaban using population pharmacokinetic (PPK) and physiologically based pharmacokinetic (PBPK) analyses. PPK analysis showed that the ABCB1 genotype, as well as renal function, were intrinsic factors of rivaroxaban pharmacokinetics in patients. This analysis also indicated that concomitant febuxostat as well as the ABCG2 genotypes and renal function were considered to be important factors affecting apixaban pharmacokinetics. PBPK analysis suggested that the relative contribution of the P-gp mediated transport to apixaban pharmacokinetics in human could be approximately equivalent to that of the BCRP mediated transport to its pharmacokinetics.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では、血液凝固第Xa因子阻害薬の個別化薬物療法の実践に向けた基盤構築を最終目標に、血液凝固第Xa因子阻害薬の体内動態の制御機構と体内動態に対する組織の寄与について解析した。その結果、リバーロキサバンの変動は患者の腎機能や薬物輸送タンパク質 (トランスポーター) の遺伝子多型で説明可能であった。また、ヒトにおけるアピキサバンの体内動態を適切に把握するには、腎機能や薬物排出トランスポーターを介した輸送の寄与を考慮する必要があることが示唆された。科学的根拠に基づく血液凝固第Xa因子阻害薬の個別化抗血栓療法を確立するための有用な情報を提供可能である。
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Report
(4 results)
Research Products
(58 results)
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[Journal Article] Incorrect holding angle of dry powder inhaler during the drug-loading step significantly decreases output efficiency2021
Author(s)
Kana Suenaga, Daiki Hira, Eri Ishido, Hiroyoshi Koide, Satoshi Ueshima, Tomoyuki Okuda, Masafumi Yamaguchi, Shin-ya Morita, Hirokazu Okamoto, Tomonobu Okano, Yasutaka Nakano, Tomohiro Terada, and Mikio Kakumoto
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Journal Title
Biological and Pharmaceutical Bulletin
Volume: -
NAID
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Peer Reviewed
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[Presentation] The ABCG2 Polymorphism, 421C>A, Modifies the Pharmacokinetics of Apixaban2021
Author(s)
Itoh H, Ueshima S, Hirata K, Hira D, Tabuchi Y, Ozawa T, Nakagawa Y, Horie M, Terada T, Katsura T
Organizer
第67回 日本不整脈心電学会学術大会
Related Report
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[Presentation] Population pharmacokinetics of edoxaban in Japanese patients with atrial fibrillation2021
Author(s)
Matsuda S, Ueshima S, Hira D, Michihata R, Tabuchi Y, Ozawa T, Itoh H, Iguchi M, Akao M, Shizuta S, Makiyama T, Nakagawa Y, Horie M, Terada T, Katsura T
Organizer
第15回 次世代を担う若手医療薬科学シンポジウム
Related Report
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[Presentation] Edoxaban Blood Concentrations vary Considerably and correlate with Anti-Factor Xa Activity in Atrial Fibrillation Patients2020
Author(s)
Minoru Horie, Satoshi Ueshima, Daiki Hira, Toshiya Katsura, Tomohiro Terada, Kouichi Kato, Tomoya Ozawa, Hideki Itoh, Yohei Tabuchi, Miya Horie, Yoshihisa Nakagawa, Takeru Makiyama, Satoshi Shizuta, Asami Kashiwa, Takanori Aizawa, Takeshi Kimura, Moritake Iguchi, Masaharu Akao
Organizer
第84回日本循環器学会学術集会
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[Presentation] Population pharmacokinetics and pharmacogenomics of rivaroxaban in Japanese patients with atrial fibrillation2020
Author(s)
Satoshi Ueshima, Daiki Hira, Kenji Kuwata , Karin Hirata, Yohei Tabuchi, Hideki Itoh , Tomoya Ozawa, Yoshihisa Nakagawa, Minoru Horie, Tomohiro Terada, and Toshiya Katsura
Organizer
第30回日本医療薬学会年会
Related Report
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[Presentation] Decreased pulmonary delivery due to incorrect holding angle of dry powder inhaler during drug loading step2020
Author(s)
Daiki Hira, Kana Suenaga, Eri Ishido, Hiroyoshi Koide, Satoshi Ueshima, Tomoyuki Okuda, Masafumi Yamaguchi, Shin-ya Morita, Hirokazu Okamoto, Tomonobu Okano, Yasutaka Nakano, Tomohiro Terada, and Mikio Kakumoto
Organizer
第30回日本医療薬学会年会
Related Report
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