Relationships between pazopanib exposure and clinical safety and efficacy in patients with advanced renal cell carcinoma.
Relationships between pazopanib exposure and clinical safety and efficacy in patients with advanced renal cell carcinoma.
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DOI：
10.1038/bjc.2014.503
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发表时间：
2014-11-11
影响因子：
8.8
通讯作者：
Pandite, L.
中科院分区：
文献类型：
--
作者：
Suttle, A. B.;Ball, H. A.;Molimard, M.;Hutson, T. E.;Carpenter, C.;Rajagopalan, D.;Lin, Y.;Swann, S.;Amado, R.;Pandite, L.
帕唑帕尼是一种靶向血管内皮生长因子受体（VEGFR）/血小板衍生生长因子受体（PDGFR）/c-Kit的口服血管生成抑制剂，已获批用于治疗局部晚期/转移性肾细胞癌（RCC）。来自晚期实体瘤和晚期/转移性RCC的试验数据用于探索血浆帕唑帕尼浓度与生物标志物变化、安全性和疗效之间的关系。首先，研究药代动力学参数与血压升高之间的关系，然后分析稳态谷浓度（Cτ）和sVEGFR 2、安全性、无进展生存期（PFS）、缓解率和肿瘤缩小。在Cτ十分位界限处比较疗效/安全性终点。观察到血压升高与Cτ之间存在强相关性（r2=0.91），而Cτ与sVEGFR 2较基线下降之间存在弱相关性（r2=0.27）。Cτ阈值>20.5 μg ml−1与疗效改善相关（PFS，P<0.004;肿瘤缩小，P<0.001），但Cτ >20.5 μg ml−1对绝对PFS或肿瘤缩小没有明显益处。然而，在整个Cτ范围内，Cτ与某些不良事件（特别是手足综合征）的相关性是连续的。有效性的阈值浓度与发生毒性的浓度重叠，尽管某些毒性在整个Cτ范围内增加。监测Cτ可以优化全身暴露，以提高临床获益并降低某些不良事件的风险。
Pazopanib, an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR)/c-Kit, is approved in locally advanced/metastatic renal cell carcinoma (RCC). Data from trials in advanced solid tumours and advanced/metastatic RCC were used to explore the relationships between plasma pazopanib concentrations and biomarker changes, safety, and efficacy. Initially, the relationships between pharmacokinetic parameters and increased blood pressure were investigated, followed by analysis of steady-state trough concentration (Cτ) and sVEGFR2, safety, progression-free survival (PFS), response rate, and tumour shrinkage. Efficacy/safety end points were compared at Cτ decile boundaries. Strong correlation between increased blood pressure and Cτ was observed (r2=0.91), whereas weak correlation was observed between Cτ and decline from baseline in sVEGFR2 (r2=0.27). Cτ threshold of >20.5 μg ml−1 was associated with improved efficacy (PFS, P<0.004; tumour shrinkage, P<0.001), but there was no appreciable benefit in absolute PFS or tumour shrinkage from Cτ >20.5 μg ml−1. However, the association of Cτ with certain adverse events, particularly hand–foot syndrome, was continuous over the entire Cτ range. The threshold concentration for efficacy overlaps with concentrations at which toxicity occurs, although some toxicities increase over the entire Cτ range. Monitoring Cτ may optimise systemic exposure to improve clinical benefit and decrease the risk of certain adverse events.
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