Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: Results from a phase I study
Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: Results from a phase I study
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DOI：
10.1200/jco.2005.04.143
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发表时间：
2005-08-20
影响因子：
45.3
通讯作者：
Herbst, RS
中科院分区：
文献类型：
--
作者：
Liu, G;Rugo, HS;Herbst, RS
目的在评价新化合物如血管生成抑制剂时，确定合适的生物活性标记物以优化治疗剂量和方案是重要的。在这里，我们提出的药效学反应，急性剂量的AG-013736测量动态对比增强磁共振成像QCE-MRI）Patients and Methods 36例晚期实体瘤患者进行了治疗与不同剂量的AG-013736。除了客观疾病缓解和药代动力学分析的标准指标外，还在基线时对26例患者进行了DCE-MRI扫描，并在第1周期-第2天AG-013736计划早晨给药后重复进行扫描。血管反应的指标，如体积转移常数（K-transs）和初始曲线下面积（IAUC）进行计算，以评估治疗对肿瘤血管function.Results可评价的血管反应数据中获得17（65%）的26例。发现线性相关性，其中K-transs和IAUC从基线至第2天的百分比变化与AG-013736暴露量成反比。使用保守的先验假设，即K-反式减少>= 50%表示客观血管反应，实现了K-反式减少50%，对应于血浆AUC（0-24）> 200 ng（.）h/mL。结论通过常规毒性标准，在选择用于额外的11期试验的剂量下观察到肿瘤血管参数的充分降低。此外，使用DCE-MRI测量的第2天血管反应似乎是药物药理学的有用指标，需要进行额外的研究以确定其是否是预测临床活性的合适标志物。
Purpose Identifying suitable markers of biologic activity is important when assessing novel compounds such as angiogenesis inhibitors to optimize the dose and schedule of therapy. Here we present the pharmacodynamic response to acute dosing of AG-013736 measured by dynamic contrast-enhanced magnetic resonance imaging QCE-MRI).Patients and Methods Thirty-six patients with advanced solid tumors were treated with various doses of AG-013736. In addition to standard measures of objective disease response and pharmacokinetic analysis, DCE-MRI scans were acquired at baseline and repeated at cycle 1-day 2 after the scheduled morning dose of the AG-013736 in 26 patients. Indicators of a vascular response, such as the volume transfer constant (K-trans) and initial area under the curve (IAUC) were calculated to assess the effect of treatment on tumor vascular function.Results Evaluable vascular response data were obtained in 17 (65%) of 26 patients. A linear correlation was found in which the percentage change from baseline to day 2 in K-trans and IAUC was inversely proportional to AG-013736 exposure. Using a conservative a priori assumption that a >= 50% decrease in K-trans. was indicative of an objective vascular response, a 50% decrease in K-trans, was achieved and corresponded to a plasma AUC(0-24) of > 200 ng (.) h/mL.Conclusion A sufficient decrease in tumor vascular parameters was observed at a dose chosen for additional phase 11 testing by conventional toxicity criteria. In addition, the day 2 vascular response measured using DCE-MRI seems to be a useful indicator of drug pharmacology, and additional research is needed to determine if it is a suitable marker for predicting clinical activity.