Renal toxicities of small molecular agents

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16417
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Nagoya City University
• Principal Investigator: Sanagawa Akimasa 名古屋市立大学, 大学院薬学研究科, 助教 (20827670)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 薬剤性腎障害 / データベース / 低分子化合物 / キナーゼ阻害剤 / 細胞毒性

Outline of Final Research Achievements

This study assesses the occurrence of acute kidney injury (AKI) in association with combination therapy drugs that are presently used to treat melanoma with a rapidly accelerated fibrosarcoma kinase B (BRAF) mutant. Specifically, we were focused on the potential nephrotoxicity of two BRAF inhibitors, vemurafenib and dabrafenib in real-world setting and human kidney cells. The real-world data were retrieved from the Food and Drug Administration Adverse Events Reporting System database. We found that the AKI risk values associated with vemurafenib were higher than those associated with dabrafenib and trametinib. Vemurafenib also lowered the cell viability and increased cell death in renal tubular epithelial cells and glomerular epithelial cells. This finding means that careful monitoring for clinical signs of kidney injury is recommended in patients treated with vemurafenib.

Free Research Field

医療薬学

Academic Significance and Societal Importance of the Research Achievements

研究成果の学術的意義：ベムラフェニブとダブラフェニブは同じBRAFを標的とする薬剤でありながら、腎毒性には大きな差が生じました。この差にはBRAF以外の分子が関与している可能性が強く疑われます。この分子と化合物の構造をつなぐ知見が明らかになれば、がん治療の安全性を向上させることができると考えられます。
社会的意義：ベムラフェニブは承認当初は腎毒性はそれほど危惧されていなかった薬剤であり、適応がん種は限定されていました。しかしながら、近年ベムラフェニブは悪性黒色腫以外のBRAF変異を有するがんにおいて大規模治験がおこなわれています。臨床の使用時には腎障害の発症に特に注意を払うべきであると考えます。