Elucidation of pharmacokinetic variability of activated factor X inhibitor for individualized pharmacotherapy

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07234
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Ritsumeikan University
• Principal Investigator: UESHIMA Satoshi 立命館大学, 薬学部, 准教授 (70734771)
• Project Period (FY): 2019-04-01 – 2022-03-31
• 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

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.

Free Research Field

薬物動態学

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。