文章：

在靶向治疗时代确定药物剂量：安全（还是不安全）行事？

Determining drug dose in the era of targeted therapies: playing it (un)safe?

原文发布日期：2022-08-23

DOI: 10.1038/s41408-022-00720-7

类型: Review Article

开放获取: 是

英文摘要：

Targeted therapies against phosphatidylinositol 3-kinase (PI3K), Bruton’s tyrosine kinase (BTK), and B-cell lymphoma-2 (BCL-2) are approved for chronic lymphocytic leukemia (CLL). Since approval of the first-in-class drugs, next-generation agents have become available and are continuously under development. While these therapies act on well-characterized molecular targets, this knowledge is only to some extent taken into consideration when determining their dose in phase I trials. For example, BTK occupancy has been assessed in dose-finding studies of various BTK inhibitors, but the minimum doses that result in full BTK occupancy were not determined. Although targeted agents have a different dose–response relationship than cytotoxic agents, which are more effective near the maximum tolerated dose, the traditional 3 + 3 toxicity-driven trial design remains heavily used in the era of targeted therapies. If pharmacodynamic biomarkers were more stringently used to guide dose selection, the recommended phase II dose would likely be lower as compared to the toxicity-driven selection. Reduced drug doses may lower toxicity, which in some cases is severe for these agents, and are supported by retrospective studies demonstrating non-inferior outcomes for patients with clinically indicated dose reductions. Here, we review strategies that were used for dose selection in phase I studies of currently approved and select investigational targeted therapies in CLL, and discuss how our initial clinical experience with targeted therapies have pointed to dose reductions, intermittent dosing, and drug combinations as strategies to overcome treatment intolerance and resistance.
 

摘要翻译： 

针对磷脂酰肌醇3-激酶（PI3K）、布鲁顿酪氨酸激酶（BTK）和B细胞淋巴瘤-2（BCL-2）的靶向疗法已获批准用于慢性淋巴细胞白血病（CLL）的治疗。自首创药物获批以来，新一代药物相继问世并持续开发中。尽管这些疗法作用于已明确表征的分子靶点，但在Ⅰ期试验确定其剂量时，相关科学认知仅得到有限考虑。例如，在不同BTK抑制剂的剂量探索研究中已评估了BTK占据率，但尚未确定实现完全BTK占据所需的最低剂量。虽然靶向药物与细胞毒药物具有不同的剂量-反应关系（后者在接近最大耐受剂量时疗效更强），传统的3+3毒性驱动试验设计在靶向治疗时代仍被广泛使用。若更严格地应用药效学生物标志物指导剂量选择，Ⅱ期推荐剂量可能会低于毒性驱动选择的剂量。降低药物剂量可减轻毒性（某些情况下这些药物的毒性较为严重），回顾性研究也支持这一观点，表明临床指示性剂量降低患者的疗效并未减弱。本文综述了当前已获批及部分在研CLL靶向疗法Ⅰ期研究中采用的剂量选择策略，并探讨靶向治疗的初步临床经验如何指向通过降低剂量、间歇给药及联合用药等策略来克服治疗不耐受和耐药性问题。

原文链接：

Determining drug dose in the era of targeted therapies: playing it (un)safe?