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

• 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
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• 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 / HLA / 手足症候群 / VFGF-A / ケラチノサイト / マウス / ハプロタイプ / VEGFR-2 / グレード3 / 遺伝子多型 / HLA遺伝子 / 脂質メタボロミックス / 活性代謝物M-2 / 活性代謝物M-5 / 相対治療強度 / 治療中止 / 体内動態 / 活性代謝物

Outline of Research at the Start

血液中の薬物は血漿蛋白質と結合して全身を循環し、一部は遊離形として存在する。薬物の効果や副作用を発現するのは遊離形である。しかし遊離形の解析は煩雑であり、あまり行われない。我々は抗がん薬レゴラフェニブの前向き臨床研究において、レゴラフェニブが体内で代謝されて生じる活性代謝物の遊離形血漿中濃度が、親化合物と比較して高いことを見出した。レゴラフェニブの治療効果や毒性の本体は、親化合物ではなく活性代謝物である可能性を示す。そこで、活性代謝物の遊離形血漿中濃度を基準とした体内動態が、治療効果や手足症候群など高頻度に認められる毒性とどのように関係するのかについて解明する。

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.

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。

Research Products

• [Journal Article] Adeno-associated virus-mediated knockdown demonstrates the major role of hepatic Bcrp in the overall disposition of the active metabolite of the tyrosine kinase inhibitor regorafenib in mice. (2023)
  • Author(s): Al-Shammari AH, Masuo Y, Yoshino S, Yamashita R, Ishimoto T, Fujita K, Kato Y.
  • Journal Title: Drug Metab Pharmacokinet Volume: 49 Pages: 100483-100483
  • DOI: 10.1016/j.dmpk.2022.100483
  • Peer Reviewed
• [Journal Article] Discrimination of hand-foot skin reaction caused by tyrosine kinase inhibitors based on direct keratinocyte toxicity and vascular endothelial growth factor receptor-2 inhibition (2022)
  • Author(s): Hasan Alshammari A, Masuo Y, Fujita KI, Shimada K, Iida N, Wakayama T, Kato Y
  • Journal Title: Biochamical Pharmacology Volume: 印刷中 Pages: 114914-114914
  • DOI: 10.1016/j.bcp.2022.114914
  • Peer Reviewed
• [Journal Article] Higher Systemic Exposure to Unbound Active Metabolites of Regorafenib Is Associated With Short Progression-Free Survival in Colorectal Cancer Patients. (2020)
  • Author(s): Kubota Y, Fujita KI, Takahashi T, Sunakawa Y, Ishida H, Hamada K, Ichikawa W, Tsunoda T, Shimada K, Masuo Y, Kato Y, Sasaki Y.
  • Journal Title: Clin Pharmacol Ther Volume: - Issue: 3 Pages: 586-595
  • DOI: 10.1002/cpt.1810
  • Peer Reviewed
• [Presentation] Associations of polymorphisms in CCL4L1 with regorafenib-induced hand-foot skin reaction in colorectal cancer patients. (2023)
  • Author(s): Koutaro Ono, Remi Murase, Natsumi Matsumoto, Yutaro Kubota, Hiroo Ishida, Takuya Tsunoda, Yasutsuna Sasaki, Ken-ichi Fujita
  • Organizer: The 20th Japanese Society of Medical Oncology annual meeting
• [Presentation] Investigation of the role of hepatic Bcrp by using adeno-associated virus mediated gene knockdown. (2022)
  • Author(s): Shotaro Yoshino, Yusuke Masuo, Reiya Yamashita, Ken-ichi Fujita, Yukio Kato
  • Organizer: 37th Japanese Society for the Study of Xenobiotics annual meeting
• [Presentation] Associations of HLA-C*01:02 and HLA-B*46:01 with regorafenib-induced erythema multiforme in Japanese patients with colorectal cancer (2022)
  • Author(s): Kosuke Takeshima, Natsumi Matsumoto, Yutaro Kubota, Hiroo Ishida, Takuya Tsunoda, Yasutsuna Sasaki, Ken-ichi Fujita
  • Organizer: 123rd American Society for Clinical Pharmacology and Therapeutics annual meeting
  • Int'l Joint Research
• [Presentation] Regorafenib-induced erythema multiforme is associated with HLA-C*01:02 and HLA-B*46:01 in Japanese cancer patients (2021)
  • Author(s): Natsumi Matsumoto, Kosuke Takeshima, Yutaro Kubota, Hiroo Ishida, Takuya Taunoda, Yasutsuna Sasaki, Ken-ichi Fujita
  • Organizer: The 19th Japanese Society of Medical Oncology annual meeting
• [Presentation] High unbound plasma concentration of M-2, an active metabolite, is associated with shorter survival in patients with metastatic colorectal cancer who received regorafenib (2019)
  • Author(s): Yutaro Kubota, Ken-ichi Fujita, Takehiro Takahashi, Yu Sunakawa, Hiroo Ishida, Kazuyuki Hamada, Wataru Ichikawa, Takuya Tsunoda, Yusuke Masuo, Yukio Kato, Yasutsuna Sasaki
  • Organizer: 110th American Association for Cancer Research annual meeting
  • Int'l Joint Research