Kitagaki Hiroe, Takeda Kentaro, Murai Kazuya, Maeda Hideki
Regulatory Science, Graduate School of Pharmaceutical Science, Meiji Pharmaceutical University, Tokyo, Japan.
Early Clinical Development Clinical Operations, Astellas Pharma Inc., Tokyo, Japan.
Clin Pharmacol Ther. 2025 Oct;118(4):823-830. doi: 10.1002/cpt.3722. Epub 2025 May 20.
Optimal dosing of oncological drugs is historically determined based on the "higher is better" paradigm. However, a paradigm shift in optimal dose selection has occurred in the development of new modalities, including molecularly targeted drugs, antibody drugs, and immunotherapies. In 2021, Project Optimus was launched by the Food and Drug Administration Oncology Center of Excellence to reform the dose optimization and dose selection paradigm in oncology drug development. In August 2024, "Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases" was published, encouraging randomized evaluation of the benefit/risk profile of a range of doses before initiating a registration trial. Although Project Optimus offers general guidance on dose optimization, it does not specify which early clinical data requires a more cautious approach to dose optimization. This is the first comprehensive study to investigate newly approved oncology drugs by the FDA over a long period and to identify the risk factors for postmarketing requirement or commitment to dose optimization, using logistic regression analysis. Our findings show that when the labeled dose is the maximum tolerated dose, the percentage of adverse reactions leading to treatment discontinuation is increased, and an exposure-safety relationship is established, the risk for postmarketing requirement or commitment to dose optimization is increased. Our study will provide actionable, data-driven insights into dose optimization strategies by objectively and quantitatively evaluating risk factors. These findings will serve as valuable guidance for designing more effective early-phase trials, complementing the FDA Project Optimus guidance.
从历史上看，肿瘤药物的最佳剂量是基于“越高越好”的范式来确定的。然而，在包括分子靶向药物、抗体药物和免疫疗法在内的新疗法的开发中，最佳剂量选择已经发生了范式转变。2021年，美国食品药品监督管理局卓越肿瘤中心发起了擎天柱项目，以改革肿瘤药物开发中的剂量优化和剂量选择范式。2024年8月，《优化用于治疗肿瘤疾病的人用处方药和生物制品的剂量》发表，鼓励在启动注册试验之前对一系列剂量的获益/风险概况进行随机评估。尽管擎天柱项目提供了关于剂量优化的一般指导，但它没有具体说明哪些早期临床数据需要在剂量优化时采取更谨慎的方法。这是第一项通过逻辑回归分析对美国食品药品监督管理局长期以来新批准的肿瘤药物进行全面研究，并确定上市后需要或承诺进行剂量优化的风险因素的研究。我们的研究结果表明，当标记剂量为最大耐受剂量时，导致治疗中断的不良反应百分比会增加，并且建立了暴露-安全性关系，那么上市后需要或承诺进行剂量优化的风险就会增加。我们的研究将通过客观和定量地评估风险因素，为剂量优化策略提供可操作的、数据驱动的见解。这些发现将为设计更有效的早期试验提供有价值的指导，补充美国食品药品监督管理局擎天柱项目的指导。
