| Project/Area Number |
16K08400
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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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| Research Field |
Medical pharmacy
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| Research Institution | Kobe University |
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Principal Investigator |
Yano Ikuko 神戸大学, 医学部附属病院, 教授 (50273446)
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| Research Collaborator |
ITOHARA Kotaro
INOUE Miho
YAMAMOTO Kazuhiro
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 生理学薬物動態モデル / 母集団解析 / タクロリムス / 生体肝移植 / CYP3A5 / PBPK / NONMEM / 腎移植 / CYP2C19 / トリクロエタノール / 小児 / 発達 / 薬学 / 薬理学 / 臨床 |
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| Outline of Final Research Achievements |
In adult patients after living-donor liver transplantation (LDLT), postoperative days and CYP3A5 genotype are known to affect tacrolimus pharmacokinetics. We constructed a physiologically based pharmacokinetic (PBPK) model adapted to the clinical data, and evaluated the contribution of liver regeneration as well as hepatic and intestine CYP3A5 genotypes on tacrolimus pharmacokinetics. As a result, liver function recovered immediately and affected the total body clearance of tacrolimus during only limited periods after LDLT. The constructed PBPK model clarified the oral clearance of tacrolimus was affected by the CYP3A5 genotypes in both the liver and intestine to the same extent. The recommended initial dosage of tacrolimus guided by genotype using PBPK simulations would be useful to maintain the therapeutic range quickly.
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| Academic Significance and Societal Importance of the Research Achievements |
臨床薬物動態パラメータの推定法として，患者の薬物血中濃度データを母集団解析等を用いて解析するTop-downアプローチと，in vitroデータや文献データを生理学的薬物動態（PBPK）モデルに適用するBottom-upアプローチがある．本研究は，PBPKモデルを基本に臨床データとの適合性を考慮したMiddle-outアプローチを用い，生体肝移植患者における移植肝の再生と肝・小腸CYP3A5遺伝子多型がタクロリムス薬物動態に与える影響を定量的に評価した点で学術的に意義深い．さらに，肝および小腸CYP3A5遺伝子多型別の投与量ノモグラムを作成した点で，臨床的にも価値がある．
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