| Project/Area Number |
20K16068
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 47060:Clinical pharmacy-related
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| Research Institution | National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders |
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Principal Investigator |
Yoshiaki Yamamoto 独立行政法人国立病院機構(静岡・てんかん神経医療センター臨床研究部), その他部局等, その他 (60596245)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
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| Keywords | てんかん / 薬物動態 / 有害事象 / 血中濃度モニタリング / 薬物相互作用 / 小児 / 稀少てんかん |
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| Outline of Research at the Start |
現在市販されている抗てんかん薬の大半は，乳幼児期に発症したてんかんと希少てんかんに対する使用経験が乏しく，安全性と有効性は確立されていない．本研究は，血中濃度モニタリングに基づき，小児てんかん患者の体内動態に与える影響因子を同定し，血中濃度と有害事象，薬剤応答の関連性を検討する．さらに，遺伝子解析に基づく抗てんかん薬の個別化治療法を確立して，小児てんかんの薬物治療法の最適化を目指す．
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| Outline of Final Research Achievements |
This study evaluated the pharmacokinetics, safety and therapeutic concentration ranges of rufinamide and levetiracetam. Rufinamide exhibited linear pharmacokinetics. Use of phenytoin, carbamazepine, and phenobarbital reduced rufinamide concentrations by 43.4%, 13.2%, and 30.3%, respectively. By contrast, concomitant use of valproate significantly elevated rufinamide concentrations. The therapeutic concentration range was 13 to 27 μg/mL When patients had a concentration greater than 20 μg/mL, the incidence risk of adverse events increased by 8.6-fold. In contrast, levetiracetam pharmacokinetics are significantly different between infant and preschool children. Preschool children had the highest levetiracetam clearance and tended to show a decrease in the ratio from age 2 to 5 years. The mean concentration was 26.9 %, and 39.3 % higher in primary school children and adolescents with chronic kidney disease. The therapeutic concentration range was 11 to 32 μg/mL.
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| Academic Significance and Societal Importance of the Research Achievements |
てんかん患者の約60%は15歳以前に発病し，0～1歳の発病率が最も高い．小児期発症のてんかんの中には，レノックス・ガストー症候群，ドラベ症候群など乳幼児期にてんかん性脳症を生じて重度の脳機能障害を来す稀少難治てんかんも含まれる．本研究は，大規模な症例集積によりルフィナミドおよびレベチラセタムの薬物動態を解明し，最適血中濃度域を同定した．今後ペランパネル，ラコサミドに関してもエビデンス蓄積し，国内外の小児てんかん患者の予後改善，QOL向上に貢献できると考える．
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