Clinical impact of unbound-base pharmacokinetics of active metabolites of a tyrosine kinase inhibitor regorafenib

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07204
• 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: Showa University
• Principal Investigator: Fujita Ken-ichi 昭和大学, 薬学部, 教授 (60281820)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: レゴラフェニブ / 遊離形血漿中濃度 / 無増悪生存期間 / 治療強度 / AUC / ABCG2 / 副作用 / 多形紅斑

Outline of Final Research Achievements

Regorafenib treatment improves survival of patients with metastatic colorectal cancer, but it is also characterized by detrimental side effects that may require modified dosing or interval schedules. Regorafenib is metabolized by cytochrome P450 3A4 in the liver to its active metabolites, M-2 and M-5. We examined area under the unbound plasma concentration-time curve (AUCu) to these compounds to establish pharmacokinetic bases for individualized dosing strategies. The plasma protein binding of M-2 and M-5 was approximately 10-fold lower than that of regorafenib, whereas AUCu values for active metabolites on both days 1 and 15 were significantly higher than that of regorafenib. Patients with higher AUCu values of M-2 or M-5 on day 1 showed significantly shorter progression-free survival than others, likely due, at least in part, to treatment discontinuation as a result of adverse events, especially occurred during first cycle.

Free Research Field

抗悪性腫瘍薬の臨床薬理学

Academic Significance and Societal Importance of the Research Achievements

著者らは、レゴラフェニブの薬効と毒性を支配するのは、親化合物ではなく、遊離形の活性代謝物M-2とM-5への曝露量であることを見出した。これらは世界初の知見である。また、体重がこれらの遊離形活性代謝物への曝露量と有意に相関したため、レゴラフェニブは160 mgの固定用量ではなく、体重に基づいた用量の設定が適切である可能性が示された。これらの結果は、現在固定用量で投与されている他のチロシンキナーゼ阻害薬の投与戦略をも変える可能性がある。以上本研究では、レゴラフェニブを含むチロシンキナーゼ阻害薬の毒性を回避し、治療効果を維持するための至適投与法の構築に必要な薬物動態学的基盤の一端を確立した。